<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/NCT04402190</url>
  </required_header>
  <id_info>
    <org_study_id>IPSO-URG</org_study_id>
    <nct_id>NCT04402190</nct_id>
  </id_info>
  <brief_title>Hypotonic Hyponatremia: Criteria for the Correct Classification of Its Etiology and of Patient Volume Status</brief_title>
  <official_title>Hypotonic Hyponatremia: Criteria for the Correct Classification of Its Etiology and of Patient Volume Status at the Access in the Emergency Department and at the Subsequent Re-evaluation in Hospital Wards</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Ospedaliera Città della Salute e della Scienza di Torino</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Azienda Ospedaliera Città della Salute e della Scienza di Torino</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>
      Hyponatremia is the most frequent electrolyte disorder encountered in clinical practice. The&#xD;
      patient approach, however, is still problematic, above all because hyponatremia is a&#xD;
      manifestation correlated to various pathological conditions, with complex etiopathogenesis.&#xD;
&#xD;
      Even though some algorithms have been proposed to correctly assess hyponatremia subtype&#xD;
      classification and patient volume status, there is no single parameter that has proven to be&#xD;
      able alone to perfectly achieve this result.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hyponatremia is the most frequent electrolyte disorder encountered in clinical practice and&#xD;
      is often associated with increased mortality, morbidity and risk of hospitalization. The&#xD;
      patient approach, however, is still problematic, above all because hyponatremia is a&#xD;
      manifestation correlated to various pathological conditions, with complex etiopathogenesis.&#xD;
&#xD;
      The most commonly used classification of hypotonic hyponatremia is, nowadays, the one&#xD;
      described in a famous review by Kumar and Berl (see Bibliography). Probably the most crucial&#xD;
      point in this classification is represented by the correct assessment of Extracellular Fluid&#xD;
      Volume Status (i.e. hypovolemia, euvolemia, hypervolemia).&#xD;
&#xD;
      Even though some algorithms have been proposed to correctly assess hyponatremia subtype&#xD;
      classification and patient volume status, there is no single parameter that has proven to be&#xD;
      able alone to perfectly achieve this result.&#xD;
&#xD;
      In the current study, the reference test (gold standard) for the definitive assessment of&#xD;
      hyponatremia subtype classification and patient volume status was a post-discharge&#xD;
      re-evaluation of all the available evidence (with the exception of plasma copeptin levels)&#xD;
      carried out by two independent neuroendocrinologists with specific expertise in sodium&#xD;
      disorders. In case of disagreement, the experts proceeded to a discussion and comparison of&#xD;
      their opinions, in order to produce a shared one.&#xD;
&#xD;
      Using this gold standard, the main aims of this observational prospective study were:&#xD;
&#xD;
        1. to estimate the diagnostic accuracy of the clinicians in identifying the subtype of&#xD;
           hyponatremia at the first evaluation of the patients in the ED and then at the admission&#xD;
           to the wards;&#xD;
&#xD;
        2. to evaluate the diagnostic accuracy of the most important methods suggested by the&#xD;
           literature (clinical, imaging, biochemical) for the assessment of Extracellular Fluid&#xD;
           Volume.&#xD;
&#xD;
      In addition to this, in recent years copeptin has been shown to be a promising parameter for&#xD;
      the evaluation of sodium disorders and water imbalances, but its diagnostic role in the&#xD;
      setting of hyponatremic patients is still largely unknown. Therefore, a secondary objective&#xD;
      of the study was to specifically evaluate the utility of copeptin (whose values - as&#xD;
      specified before - were hidden to the neuroendocrinologists in charge of defining the gold&#xD;
      standard diagnoses for each patient) for the assessment of hyponatremia subtype&#xD;
      classification and patient volume status.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 1, 2018</start_date>
  <completion_date type="Actual">February 28, 2020</completion_date>
  <primary_completion_date type="Actual">August 31, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Subtype classification of hypotonic hyponatremia according to the overall judgment of the clinical case by the point-of-care clinician</measure>
    <time_frame>At ED admission</time_frame>
    <description>The point-of-care clinician was asked to provide a subtype classification of hypotonic hyponatremia according to his/her overall judgment of the clinical case (using Kumar and Berl classification classes as a reference frame). This will be compared to the gold standard reference (as defined in the &quot;Study Description&quot; Section). The strength of agreement (by Cohen's kappa) and the accuracy will thus be evaluated.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Subtype classification of hypotonic hyponatremia according to the overall judgment of the clinical case by the point-of-care clinician</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>The point-of-care clinician was asked to provide a subtype classification of hypotonic hyponatremia according to his/her overall judgment of the clinical case (using Kumar and Berl classification classes as a reference frame). This will be compared to the gold standard reference (as defined in the &quot;Study Description&quot; Section). The strength of agreement (by Cohen's kappa) and the accuracy will thus be evaluated.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Physical Examination (PE) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Elements of PE relevant for ECF Volume Status assessment were recorded (blood pressure, heart rate, pulmonary crepitations/rales, jugular vein distension, peripheral edema, dry mucous membranes). The overall evaluation of ECF Volume Status based on PE alone will be compared to the gold standard reference (as defined in the &quot;Study Description&quot; Section).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Physical Examination (PE) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>Elements of PE relevant for ECF Volume Status assessment were recorded (blood pressure, heart rate, pulmonary crepitations/rales, jugular vein distension, peripheral edema, dry mucous membranes). The overall evaluation of ECF Volume Status based on PE alone will be compared to the gold standard reference (as defined in the &quot;Study Description&quot; Section).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inferior Vena Cava (IVC) ultrasound evaluation as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>IVC diameter and collapsibility were recorded. The overall evaluation of ECF Volume Status based on IVC ultrasound evaluation alone will be compared to the gold standard reference (as defined in the &quot;Study Description&quot; Section).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inferior Vena Cava (IVC) ultrasound evaluation as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>IVC diameter and collapsibility were recorded. The overall evaluation of ECF Volume Status based on IVC ultrasound evaluation alone will be compared to the gold standard reference (as defined in the &quot;Study Description&quot; Section).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum creatinine as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Serum creatinine (mg/dl) will be used to estimate GFR (ml/min) according to CKD-EPI formula. eGFR will then be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum urea as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Serum urea (mg/dl) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum urea / serum creatinine ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Serum urea / serum creatinine ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Urine sodium as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Urine sodium (mmol/L), evaluated on a spot sample, will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Urine sodium / urine osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Urine sodium / urine osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Urine sodium / plasma osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Urine sodium / plasma osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum NT-proBNP as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Serum NT-proBNP (pg/ml) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum NT-proBNP / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Serum NT-proBNP / urine sodium ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum creatinine as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>Serum creatinine (mg/dl) will be used to estimate GFR (ml/min) according to CKD-EPI formula. eGFR will then be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum urea as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>Serum urea (mg/dl) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum urea / serum creatinine ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>Serum urea / serum creatinine ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Urine sodium as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>Urine sodium (mmol/L), evaluated on a spot sample, will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Urine sodium / urine osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>Urine sodium / urine osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Urine sodium / plasma osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>Urine sodium / plasma osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Plasma renin activity (PRA) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>PRA (ng/ml/h) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Uric acid as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>Uric acid (mg/dl) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma copeptin as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Plasma copeptin (pmol/L) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma copeptin / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At ED admission</time_frame>
    <description>Plasma copeptin / urine sodium ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma copeptin as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>Plasma copeptin (pmol/L) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma copeptin / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status</measure>
    <time_frame>At hospital ward admission</time_frame>
    <description>Plasma copeptin / urine sodium ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Length of hospitalization</measure>
    <time_frame>Up to 6 months after ED admission</time_frame>
    <description>The length of hospitalization will be compared across subgroups according to hyponatremia subtype classification. As already previously described, these subgroups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </other_outcome>
  <other_outcome>
    <measure>Overall mortality</measure>
    <time_frame>Up to 6 months after ED admission</time_frame>
    <description>All deaths occurring during hospitalization and/or within 6 months after hospital discharge will be registered. The overall mortality will be compared across subgroups (using a survival analysis model) according to hyponatremia subtype classification. As already previously described, these subgroups will be identified by the gold standard reference defined in the &quot;Study Description&quot; Section.</description>
  </other_outcome>
  <enrollment type="Actual">123</enrollment>
  <condition>Hyponatremia</condition>
  <condition>Hyponatremia With Extracellular Fluid Depletion</condition>
  <condition>Hyponatremia With Normal Extracellular Fluid Volume</condition>
  <condition>Hyponatremia With Excess Extracellular Fluid Volume</condition>
  <eligibility>
    <study_pop>
      <textblock>
        All consecutive patients admitted at the emergency department (ED) of our hospital in the&#xD;
        time frames specified in the inclusion criteria with a detection, at the time of ED access,&#xD;
        of moderate-severe hyponatremia (defined as serum sodium &lt; 130 mmol/L at blood gas&#xD;
        analysis).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Access to the emergency department (ED) of our hospital from Monday to Thursday,&#xD;
             between 8 am and 6 pm (time constraint needed so that all the necessary laboratory&#xD;
             analyzes could be correctly completed)&#xD;
&#xD;
          -  Detection at the time of ED access of moderate-severe hyponatremia, defined as serum&#xD;
             sodium &lt; 130 mmol/L at blood gas analysis (BGA)&#xD;
&#xD;
          -  Need for hospitalization&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Programmed hospitalization that did not include access through the ED&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ezio Ghigo, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>AOU Città della Salute e della Scienza, Torino</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>AOU Città della Salute e della Scienza</name>
      <address>
        <city>Torino</city>
        <state>Piemonte</state>
        <zip>10126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, van der Veer S, Van Biesen W, Nagler E; Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014 Feb 25;170(3):G1-47. doi: 10.1530/EJE-13-1020. Print 2014 Mar. Erratum In: Eur J Endocrinol. 2014 Jul;171(1):X1.</citation>
    <PMID>24569125</PMID>
  </reference>
  <reference>
    <citation>Fenske W, Maier SK, Blechschmidt A, Allolio B, Stork S. Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. Am J Med. 2010 Jul;123(7):652-7. doi: 10.1016/j.amjmed.2010.01.013. Erratum In: Am J Med. 2011 Oct;124(10):e9.</citation>
    <PMID>20609688</PMID>
  </reference>
  <reference>
    <citation>Fenske W, Stork S, Blechschmidt A, Maier SG, Morgenthaler NG, Allolio B. Copeptin in the differential diagnosis of hyponatremia. J Clin Endocrinol Metab. 2009 Jan;94(1):123-9. doi: 10.1210/jc.2008-1426. Epub 2008 Nov 4.</citation>
    <PMID>18984663</PMID>
  </reference>
  <reference>
    <citation>Christ-Crain M, Morgenthaler NG, Fenske W. Copeptin as a biomarker and a diagnostic tool in the evaluation of patients with polyuria-polydipsia and hyponatremia. Best Pract Res Clin Endocrinol Metab. 2016 Mar;30(2):235-47. doi: 10.1016/j.beem.2016.02.003. Epub 2016 Feb 16.</citation>
    <PMID>27156761</PMID>
  </reference>
  <reference>
    <citation>Sailer CO, Winzeler B, Nigro N, Suter-Widmer I, Arici B, Bally M, Schuetz P, Mueller B, Christ-Crain M. Characteristics and outcomes of patients with profound hyponatraemia due to primary polydipsia. Clin Endocrinol (Oxf). 2017 Nov;87(5):492-499. doi: 10.1111/cen.13384. Epub 2017 Jul 7.</citation>
    <PMID>28556237</PMID>
  </reference>
  <reference>
    <citation>Boursier G, Almeras M, Buthiau D, Jugant S, Daubin D, Kuster N, Dupuy AM, Ribstein J, Klouche K, Cristol JP. CT-pro-AVP as a tool for assessment of intravascular volume depletion in severe hyponatremia. Clin Biochem. 2015 Jul;48(10-11):640-5. doi: 10.1016/j.clinbiochem.2015.03.013. Epub 2015 Mar 28.</citation>
    <PMID>25828045</PMID>
  </reference>
  <reference>
    <citation>Nigro N, Winzeler B, Suter-Widmer I, Schuetz P, Arici B, Bally M, Blum CA, Nickel CH, Bingisser R, Bock A, Huber A, Muller B, Christ-Crain M. Evaluation of copeptin and commonly used laboratory parameters for the differential diagnosis of profound hyponatraemia in hospitalized patients: 'The Co-MED Study'. Clin Endocrinol (Oxf). 2017 Mar;86(3):456-462. doi: 10.1111/cen.13243. Epub 2016 Oct 7.</citation>
    <PMID>27658031</PMID>
  </reference>
  <reference>
    <citation>Kumar S, Berl T. Sodium. Lancet. 1998 Jul 18;352(9123):220-8. doi: 10.1016/S0140-6736(97)12169-9.</citation>
    <PMID>9683227</PMID>
  </reference>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>May 20, 2020</study_first_submitted>
  <study_first_submitted_qc>May 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 26, 2020</study_first_posted>
  <last_update_submitted>May 22, 2020</last_update_submitted>
  <last_update_submitted_qc>May 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 26, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Ospedaliera Città della Salute e della Scienza di Torino</investigator_affiliation>
    <investigator_full_name>Ezio Ghigo</investigator_full_name>
    <investigator_title>Medical Doctor, Full Professor in Endocrinology</investigator_title>
  </responsible_party>
  <keyword>Hyponatremia</keyword>
  <keyword>Hyponatremia with Extracellular Fluid Depletion</keyword>
  <keyword>Hyponatremia with Normal Extracellular Fluid Volume</keyword>
  <keyword>Hyponatremia with Excess Extracellular Fluid Volume</keyword>
  <keyword>Hypotonic Hyponatremia</keyword>
  <keyword>Volume Status</keyword>
  <keyword>Intravascular Volume Status</keyword>
  <keyword>Extracellular Fluid Volume Status</keyword>
  <keyword>Copeptin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hyponatremia</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT04402190
org study id: IPSO-URG
nct id: NCT04402190
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Hyponatremia is the most frequent electrolyte disorder encountered in clinical practice. The
      patient approach, however, is still problematic, above all because hyponatremia is a
      manifestation correlated to various pathological conditions, with complex etiopathogenesis.

      Even though some algorithms have been proposed to correctly assess hyponatremia subtype
      classification and patient volume status, there is no single parameter that has proven to be
      able alone to perfectly achieve this result.
Hyponatremia is the most frequent electrolyte disorder encountered in clinical practice and
      is often associated with increased mortality, morbidity and risk of hospitalization. The
      patient approach, however, is still problematic, above all because hyponatremia is a
      manifestation correlated to various pathological conditions, with complex etiopathogenesis.

      The most commonly used classification of hypotonic hyponatremia is, nowadays, the one
      described in a famous review by Kumar and Berl (see Bibliography). Probably the most crucial
      point in this classification is represented by the correct assessment of Extracellular Fluid
      Volume Status (i.e. hypovolemia, euvolemia, hypervolemia).

      Even though some algorithms have been proposed to correctly assess hyponatremia subtype
      classification and patient volume status, there is no single parameter that has proven to be
      able alone to perfectly achieve this result.

      In the current study, the reference test (gold standard) for the definitive assessment of
      hyponatremia subtype classification and patient volume status was a post-discharge
      re-evaluation of all the available evidence (with the exception of plasma copeptin levels)
      carried out by two independent neuroendocrinologists with specific expertise in sodium
      disorders. In case of disagreement, the experts proceeded to a discussion and comparison of
      their opinions, in order to produce a shared one.

      Using this gold standard, the main aims of this observational prospective study were:

        1. to estimate the diagnostic accuracy of the clinicians in identifying the subtype of
           hyponatremia at the first evaluation of the patients in the ED and then at the admission
           to the wards;

        2. to evaluate the diagnostic accuracy of the most important methods suggested by the
           literature (clinical, imaging, biochemical) for the assessment of Extracellular Fluid
           Volume.

      In addition to this, in recent years copeptin has been shown to be a promising parameter for
      the evaluation of sodium disorders and water imbalances, but its diagnostic role in the
      setting of hyponatremic patients is still largely unknown. Therefore, a secondary objective
      of the study was to specifically evaluate the utility of copeptin (whose values - as
      specified before - were hidden to the neuroendocrinologists in charge of defining the gold
      standard diagnoses for each patient) for the assessment of hyponatremia subtype
      classification and patient volume status.
observational model: Cohort
time perspective: Prospective
measure: Subtype classification of hypotonic hyponatremia according to the overall judgment of the clinical case by the point-of-care clinician
time frame: At ED admission
description: The point-of-care clinician was asked to provide a subtype classification of hypotonic hyponatremia according to his/her overall judgment of the clinical case (using Kumar and Berl classification classes as a reference frame). This will be compared to the gold standard reference (as defined in the "Study Description" Section). The strength of agreement (by Cohen's kappa) and the accuracy will thus be evaluated.
measure: Subtype classification of hypotonic hyponatremia according to the overall judgment of the clinical case by the point-of-care clinician
time frame: At hospital ward admission
description: The point-of-care clinician was asked to provide a subtype classification of hypotonic hyponatremia according to his/her overall judgment of the clinical case (using Kumar and Berl classification classes as a reference frame). This will be compared to the gold standard reference (as defined in the "Study Description" Section). The strength of agreement (by Cohen's kappa) and the accuracy will thus be evaluated.
measure: Physical Examination (PE) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Elements of PE relevant for ECF Volume Status assessment were recorded (blood pressure, heart rate, pulmonary crepitations/rales, jugular vein distension, peripheral edema, dry mucous membranes). The overall evaluation of ECF Volume Status based on PE alone will be compared to the gold standard reference (as defined in the "Study Description" Section).
measure: Physical Examination (PE) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: Elements of PE relevant for ECF Volume Status assessment were recorded (blood pressure, heart rate, pulmonary crepitations/rales, jugular vein distension, peripheral edema, dry mucous membranes). The overall evaluation of ECF Volume Status based on PE alone will be compared to the gold standard reference (as defined in the "Study Description" Section).
measure: Inferior Vena Cava (IVC) ultrasound evaluation as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: IVC diameter and collapsibility were recorded. The overall evaluation of ECF Volume Status based on IVC ultrasound evaluation alone will be compared to the gold standard reference (as defined in the "Study Description" Section).
measure: Inferior Vena Cava (IVC) ultrasound evaluation as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: IVC diameter and collapsibility were recorded. The overall evaluation of ECF Volume Status based on IVC ultrasound evaluation alone will be compared to the gold standard reference (as defined in the "Study Description" Section).
measure: Serum creatinine as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Serum creatinine (mg/dl) will be used to estimate GFR (ml/min) according to CKD-EPI formula. eGFR will then be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Serum urea as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Serum urea (mg/dl) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Serum urea / serum creatinine ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Serum urea / serum creatinine ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Urine sodium as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Urine sodium (mmol/L), evaluated on a spot sample, will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Urine sodium / urine osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Urine sodium / urine osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Urine sodium / plasma osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Urine sodium / plasma osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Serum NT-proBNP as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Serum NT-proBNP (pg/ml) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Serum NT-proBNP / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Serum NT-proBNP / urine sodium ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Serum creatinine as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: Serum creatinine (mg/dl) will be used to estimate GFR (ml/min) according to CKD-EPI formula. eGFR will then be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Serum urea as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: Serum urea (mg/dl) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Serum urea / serum creatinine ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: Serum urea / serum creatinine ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Urine sodium as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: Urine sodium (mmol/L), evaluated on a spot sample, will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Urine sodium / urine osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: Urine sodium / urine osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Urine sodium / plasma osmolality ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: Urine sodium / plasma osmolality ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Plasma renin activity (PRA) as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: PRA (ng/ml/h) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Uric acid as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: Uric acid (mg/dl) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Plasma copeptin as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Plasma copeptin (pmol/L) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Plasma copeptin / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At ED admission
description: Plasma copeptin / urine sodium ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Plasma copeptin as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: Plasma copeptin (pmol/L) will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Plasma copeptin / urine sodium ratio as a tool for the assessment of Extra-Cellular Fluid (ECF) Volume Status
time frame: At hospital ward admission
description: Plasma copeptin / urine sodium ratio will be compared between three main groups of interest (i.e. hypovolemic, euvolemic and hypervolemic patients). As already previously described, these groups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Length of hospitalization
time frame: Up to 6 months after ED admission
description: The length of hospitalization will be compared across subgroups according to hyponatremia subtype classification. As already previously described, these subgroups will be identified by the gold standard reference defined in the "Study Description" Section.
measure: Overall mortality
time frame: Up to 6 months after ED admission
description: All deaths occurring during hospitalization and/or within 6 months after hospital discharge will be registered. The overall mortality will be compared across subgroups (using a survival analysis model) according to hyponatremia subtype classification. As already previously described, these subgroups will be identified by the gold standard reference defined in the "Study Description" Section.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ezio Ghigo, MD
role: Principal Investigator
affiliation: AOU Città della Salute e della Scienza, Torino
facility: 
country: Italy
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PMID: 24569125
citation: Fenske W, Maier SK, Blechschmidt A, Allolio B, Stork S. Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. Am J Med. 2010 Jul;123(7):652-7. doi: 10.1016/j.amjmed.2010.01.013. Erratum In: Am J Med. 2011 Oct;124(10):e9.
PMID: 20609688
citation: Fenske W, Stork S, Blechschmidt A, Maier SG, Morgenthaler NG, Allolio B. Copeptin in the differential diagnosis of hyponatremia. J Clin Endocrinol Metab. 2009 Jan;94(1):123-9. doi: 10.1210/jc.2008-1426. Epub 2008 Nov 4.
PMID: 18984663
citation: Christ-Crain M, Morgenthaler NG, Fenske W. Copeptin as a biomarker and a diagnostic tool in the evaluation of patients with polyuria-polydipsia and hyponatremia. Best Pract Res Clin Endocrinol Metab. 2016 Mar;30(2):235-47. doi: 10.1016/j.beem.2016.02.003. Epub 2016 Feb 16.
PMID: 27156761
citation: Sailer CO, Winzeler B, Nigro N, Suter-Widmer I, Arici B, Bally M, Schuetz P, Mueller B, Christ-Crain M. Characteristics and outcomes of patients with profound hyponatraemia due to primary polydipsia. Clin Endocrinol (Oxf). 2017 Nov;87(5):492-499. doi: 10.1111/cen.13384. Epub 2017 Jul 7.
PMID: 28556237
citation: Boursier G, Almeras M, Buthiau D, Jugant S, Daubin D, Kuster N, Dupuy AM, Ribstein J, Klouche K, Cristol JP. CT-pro-AVP as a tool for assessment of intravascular volume depletion in severe hyponatremia. Clin Biochem. 2015 Jul;48(10-11):640-5. doi: 10.1016/j.clinbiochem.2015.03.013. Epub 2015 Mar 28.
PMID: 25828045
citation: Nigro N, Winzeler B, Suter-Widmer I, Schuetz P, Arici B, Bally M, Blum CA, Nickel CH, Bingisser R, Bock A, Huber A, Muller B, Christ-Crain M. Evaluation of copeptin and commonly used laboratory parameters for the differential diagnosis of profound hyponatraemia in hospitalized patients: 'The Co-MED Study'. Clin Endocrinol (Oxf). 2017 Mar;86(3):456-462. doi: 10.1111/cen.13243. Epub 2016 Oct 7.
PMID: 27658031
citation: Kumar S, Berl T. Sodium. Lancet. 1998 Jul 18;352(9123):220-8. doi: 10.1016/S0140-6736(97)12169-9.
PMID: 9683227
responsible party type: Principal Investigator
investigator affiliation: Azienda Ospedaliera Città della Salute e della Scienza di Torino
investigator full name: Ezio Ghigo
investigator title: Medical Doctor, Full Professor in Endocrinology
mesh term: Hyponatremia
sharing ipd: No