<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/NCT03769597</url>
  </required_header>
  <id_info>
    <org_study_id>87RI18_0007 (DFG HEP)</org_study_id>
    <nct_id>NCT03769597</nct_id>
  </id_info>
  <brief_title>Description of the Evolution of Plasma and Urinary Concentrations of Iohexol in a Cirrhotic Patient Population</brief_title>
  <acronym>DFG HEP</acronym>
  <official_title>Description of the Evolution of Plasma and Urinary Concentrations of Iohexol in a Cirrhotic Patient Population: &quot;Pilot Study on 9 Patients&quot;</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Limoges</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Limoges</source>
  <oversight_info>
    <has_dmc>No</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>
      Background: It is important to accurately assess the glomerular filtration rate (GFR) of&#xD;
      patients with liver diseases, particularly cirrhosis, to deliver care and adjust the drugs'&#xD;
      posology.&#xD;
&#xD;
      Purpose: The frequency of chronic renal failure is underestimated in patients with advanced&#xD;
      liver disease and the difficulty to assess kidney failure justifies the investigator's study,&#xD;
      which aims to describe, by means of a population pharmacokinetic model, the evolution of&#xD;
      plasma and urinary concentrations of iohexol, an effective non-ionic, water-soluble contrast&#xD;
      agent which is used in radiographic procedures, in cirrhotic patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cirrhosis is often complicated by kidney failure and the prognostic value of renal function&#xD;
      (serum creatinine) during cirrhosis is included in the MELD model. In addition, chronic&#xD;
      kidney disease (15%) after liver transplantation is also an independent mortality factor.&#xD;
&#xD;
      The most commonly used methods to estimate GFR are based on creatinine, but in patients&#xD;
      suffering from advanced hepatic disease, such as cirrhosis, this parameter is incorrect, due&#xD;
      to the low creatinine production and potentially to elevated serum bilirubin and decreased&#xD;
      albumin levels. Furthermore, ascites can interfere with serum creatinine concentration. In&#xD;
      this condition, all creatinine-based evaluations of GFR overestimate gold standard-measured&#xD;
      GFR. Specific eGFR equations for liver disease or new approaches for estimating GFR may be&#xD;
      necessary.&#xD;
&#xD;
      The plasma clearance of iohexol is a recognized technique for the measurement of the&#xD;
      glomerular filtration rate (GFR).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2, 2019</start_date>
  <completion_date type="Actual">August 28, 2019</completion_date>
  <primary_completion_date type="Actual">August 28, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change of plasma concentrations of iohexol in a population of 9 cirrhotic patients from rich kinetics.</measure>
    <time_frame>0 minute, 15 minute, 30 minute, 1 hour, 90 minute, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours</time_frame>
    <description>Plasma concentration curves for iohexol according to the time.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of urinary concentrations of iohexol in a population of 9 cirrhotic patients from rich kinetics.</measure>
    <time_frame>0 minute, 4 hours, 8 hours, 12 hours, 24 hours</time_frame>
    <description>Urine concentration curves for iohexol according to the time.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Calculate the renal clearance of iohexol.</measure>
    <time_frame>0 minute, 15 minute, 30 minute, 1 hour, 90 minute, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours</time_frame>
    <description>Renal clearance of iohexol obtained by noncompartmental analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Calculate the plasma clearance of iohexol.</measure>
    <time_frame>0 minute, 15 minutes, 30 minutes, 1 hour, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours</time_frame>
    <description>Urinary clearance of iohexol obtained by noncompartmental analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Develop a pharmacokinetic model for the estimation of renal clearance from plasma clearance.</measure>
    <time_frame>0 minute, 15 minutes, 30 minutes, 1 hour, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hrs</time_frame>
    <description>The evaluation of the performance of the model will be based on its ability to predict iohexol concentrations, expressed through (%) and accuracy (root of mean bias squared = RMSE) between urinary concentrations and predicted plasma levels and urinary concentrations and observed plasma levels.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the correlation between plasma clearance of iohexol obtained by the model and The GFR estimated by (CKD-EPI formula B, MDRD4 and MDRD6 formulas C, renal clearance of cystatine C)</measure>
    <time_frame>0 minute, 24 hours</time_frame>
    <description>Linear Correlation Coefficients and Point Clouds between the plasma clearance of iohexol estimated by model and the DFGs calculated by the different methods. Bland Altman curves will also be drawn.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine in the model of plasmatic clearance the relevant covariates.</measure>
    <time_frame>0 minute, 24 hours</time_frame>
    <description>Evaluation of covariates by multiple linear regression and point clouds (continuous covariates) or Mann Whitney and box plots (categorical covariates). Inclusion of covariates characterized by a P &lt;0.01 in the model. Looking for covariates that will influence the relationship between plasma clearance and renal clearance : grade of intensity of ascites. 2 grades: minimal, (ultrasound) or moderate and bulky, age, weight (of the day and H24), sex, diuresis of 24 hours, albumin, natriuresis, taking diuretics (nature and dose), other drugs that can influence GFR, biological stigmata of hepatic insufficiency or portal hypertension: bilirubin, albumin, INR, phosphatases, Child Pugh score, MELD score.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Cirrhosis Renal</condition>
  <arm_group>
    <arm_group_label>Iohexol administration</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After injecting a loading dose of 5ml of Iohexol Inj 300 MG/ML bolus, blood samples will be taken at given times for 24 hours. The urinary samples will be taken at each urination, with measurement of the exact volume and times</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Iohexol Inj 300 MG/ML</intervention_name>
    <description>After injecting a loading dose of 5ml of iohexol bolus, blood samples will be taken at given times for 24 hours. The urinary samples will be taken at each urination, with measurement of the exact volume and times</description>
    <arm_group_label>Iohexol administration</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with advanced liver disease, with potential indication for liver&#xD;
             transplantation, with or without ascites :&#xD;
&#xD;
               -  No ascites: 3 patients.&#xD;
&#xD;
               -  Grade 1 (mild): ascites only detectable by ultrasound examination. 3 patients.&#xD;
&#xD;
               -  Grade 2 (moderate) and Grade 3 (wide): clinically significant ascites, causing&#xD;
                  moderate symmetrical distension of the abdomen, or causing severe abdominal&#xD;
                  distension. 3 patients.&#xD;
&#xD;
          -  Patients will be over 18 years, affiliated to a social security scheme and give their&#xD;
             informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Hypersensitivity to the active substance to the products of iodinated contrasts or to&#xD;
             any of the excipients mentioned in Composition section&#xD;
&#xD;
          -  History of major or cutaneous immediate reaction delayed injection of iodinated&#xD;
             contrast medium (Omnipaque)&#xD;
&#xD;
          -  Patients with thyrotoxicosis&#xD;
&#xD;
          -  Asthmatic patients&#xD;
&#xD;
          -  Patient with a history of dysthyroidism&#xD;
&#xD;
          -  Patients with severe cardiovascular disease&#xD;
&#xD;
          -  Patients with central nervous system disorders especially vascular&#xD;
&#xD;
          -  Patients with pheochromocytoma&#xD;
&#xD;
          -  Patients with myasthenia&#xD;
&#xD;
          -  Patients with sickle cell disease&#xD;
&#xD;
          -  Patients with autoimmune disease&#xD;
&#xD;
          -  Patients treated with metformin&#xD;
&#xD;
          -  Patients requiring anesthesia on the first day of levies&#xD;
&#xD;
          -  Patients with an injection of iodine contrast during hospitalization and in both&#xD;
             previous weeks. Gadolinium injections are not not contraindicated&#xD;
&#xD;
          -  Patients under guardianship or curatorship or incapacitated give informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University Hospital</name>
      <address>
        <city>Limoges</city>
        <zip>87042</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>November 30, 2018</study_first_submitted>
  <study_first_submitted_qc>December 6, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 7, 2018</study_first_posted>
  <last_update_submitted>September 24, 2019</last_update_submitted>
  <last_update_submitted_qc>September 24, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 25, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cirrhosis Renal</keyword>
  <keyword>GFR</keyword>
  <keyword>renal function</keyword>
  <keyword>Bayesian model</keyword>
  <keyword>plasma clearance</keyword>
  <keyword>iohexol</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fibrosis</mesh_term>
  </condition_browse>
  <!-- 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/NCT03769597
org study id: 87RI18_0007 (DFG HEP)
nct id: NCT03769597
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Background: It is important to accurately assess the glomerular filtration rate (GFR) of
      patients with liver diseases, particularly cirrhosis, to deliver care and adjust the drugs'
      posology.

      Purpose: The frequency of chronic renal failure is underestimated in patients with advanced
      liver disease and the difficulty to assess kidney failure justifies the investigator's study,
      which aims to describe, by means of a population pharmacokinetic model, the evolution of
      plasma and urinary concentrations of iohexol, an effective non-ionic, water-soluble contrast
      agent which is used in radiographic procedures, in cirrhotic patients.
Cirrhosis is often complicated by kidney failure and the prognostic value of renal function
      (serum creatinine) during cirrhosis is included in the MELD model. In addition, chronic
      kidney disease (15%) after liver transplantation is also an independent mortality factor.

      The most commonly used methods to estimate GFR are based on creatinine, but in patients
      suffering from advanced hepatic disease, such as cirrhosis, this parameter is incorrect, due
      to the low creatinine production and potentially to elevated serum bilirubin and decreased
      albumin levels. Furthermore, ascites can interfere with serum creatinine concentration. In
      this condition, all creatinine-based evaluations of GFR overestimate gold standard-measured
      GFR. Specific eGFR equations for liver disease or new approaches for estimating GFR may be
      necessary.

      The plasma clearance of iohexol is a recognized technique for the measurement of the
      glomerular filtration rate (GFR).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change of plasma concentrations of iohexol in a population of 9 cirrhotic patients from rich kinetics.
time frame: 0 minute, 15 minute, 30 minute, 1 hour, 90 minute, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours
description: Plasma concentration curves for iohexol according to the time.
measure: Change of urinary concentrations of iohexol in a population of 9 cirrhotic patients from rich kinetics.
time frame: 0 minute, 4 hours, 8 hours, 12 hours, 24 hours
description: Urine concentration curves for iohexol according to the time.
measure: Calculate the renal clearance of iohexol.
time frame: 0 minute, 15 minute, 30 minute, 1 hour, 90 minute, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours
description: Renal clearance of iohexol obtained by noncompartmental analysis.
measure: Calculate the plasma clearance of iohexol.
time frame: 0 minute, 15 minutes, 30 minutes, 1 hour, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours
description: Urinary clearance of iohexol obtained by noncompartmental analysis.
measure: Develop a pharmacokinetic model for the estimation of renal clearance from plasma clearance.
time frame: 0 minute, 15 minutes, 30 minutes, 1 hour, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hrs
description: The evaluation of the performance of the model will be based on its ability to predict iohexol concentrations, expressed through (%) and accuracy (root of mean bias squared = RMSE) between urinary concentrations and predicted plasma levels and urinary concentrations and observed plasma levels.
measure: Evaluate the correlation between plasma clearance of iohexol obtained by the model and The GFR estimated by (CKD-EPI formula B, MDRD4 and MDRD6 formulas C, renal clearance of cystatine C)
time frame: 0 minute, 24 hours
description: Linear Correlation Coefficients and Point Clouds between the plasma clearance of iohexol estimated by model and the DFGs calculated by the different methods. Bland Altman curves will also be drawn.
measure: Determine in the model of plasmatic clearance the relevant covariates.
time frame: 0 minute, 24 hours
description: Evaluation of covariates by multiple linear regression and point clouds (continuous covariates) or Mann Whitney and box plots (categorical covariates). Inclusion of covariates characterized by a P <0.01 in the model. Looking for covariates that will influence the relationship between plasma clearance and renal clearance : grade of intensity of ascites. 2 grades: minimal, (ultrasound) or moderate and bulky, age, weight (of the day and H24), sex, diuresis of 24 hours, albumin, natriuresis, taking diuretics (nature and dose), other drugs that can influence GFR, biological stigmata of hepatic insufficiency or portal hypertension: bilirubin, albumin, INR, phosphatases, Child Pugh score, MELD score.
arm group label: Iohexol administration
arm group type: Experimental
description: After injecting a loading dose of 5ml of Iohexol Inj 300 MG/ML bolus, blood samples will be taken at given times for 24 hours. The urinary samples will be taken at each urination, with measurement of the exact volume and times
intervention type: Drug
intervention name: Iohexol Inj 300 MG/ML
description: After injecting a loading dose of 5ml of iohexol bolus, blood samples will be taken at given times for 24 hours. The urinary samples will be taken at each urination, with measurement of the exact volume and times
arm group label: Iohexol administration
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
facility: 
country: France
responsible party type: Sponsor
mesh term: Fibrosis