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    Summary
    EudraCT Number:2018-002778-35
    Sponsor's Protocol Code Number:87RI18_0008
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-09-05
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2018-002778-35
    A.3Full title of the trial
    Description of the evolution of plasma and urinary concentrations of iohexol in a cirrhotic patient population. "Pilot study on 9 patients"
    Description de l’évolution des concentrations plasmatiques et urinaires de l’iohexol dans une population de patients cirrhotiques. « Etude pilote sur 9 patients »
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Description of the evolution of plasma and urinary concentrations of iohexol in a cirrhotic patient population. "Pilot study on 9 patients"
    Description de l’évolution des concentrations plasmatiques et urinaires de l’iohexol dans une population de patients cirrhotiques. « Etude pilote sur 9 patients »
    A.3.2Name or abbreviated title of the trial where available
    DFGHep
    A.4.1Sponsor's protocol code number87RI18_0008
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCHU de Limoges
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCHU de Limoges
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportConseil régional de la Région de la Nouvelle Aquitaine
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHU de LIMOGES
    B.5.2Functional name of contact pointDirection Research and Innovation
    B.5.3 Address:
    B.5.3.1Street Address2 avenue Martin Luther King
    B.5.3.2Town/ cityLIMOGES
    B.5.3.3Post code87042
    B.5.3.4CountryFrance
    B.5.4Telephone number+33555058911
    B.5.5Fax number+33555056696
    B.5.6E-maildrc@chu-limoges.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name OMNIPAQUE
    D.2.1.1.2Name of the Marketing Authorisation holderGE HEALTHCARE SAS
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with advanced liver disease, with potential indication for liver transplantation, with or without ascites
    Patients suivis habituellement dans le service d’Hépato-Gastro-Entérologie et atteints de maladie hépatique avancée, avec indication potentielle de transplantation hépatique, avec ou sans ascite
    E.1.1.1Medical condition in easily understood language
    Patients with advanced liver disease, with potential indication for liver transplantation, with or without ascites
    Patients suivis habituellement dans le service d’Hépato-Gastro-Entérologie et atteints de maladie hépatique avancée, avec indication potentielle de transplantation hépatique, avec ou sans ascite
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10019641
    E.1.2Term Hepatic cirrhosis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Describe the evolution of plasma and urinary concentrations of iohexol in a population of 9 cirrhotic patients from rich kinetics.
    Décrire l’évolution des concentrations plasmatiques et urinaires de l’iohexol dans une population de 9 patients cirrhotiques à partir de cinétiques riches.
    E.2.2Secondary objectives of the trial
    1. Calculate the renal clearance of iohexol.
    2. Calculate the plasma clearance of iohexol.
    3. Develop a pharmacokinetic model for the estimation of renal clearance from plasma clearance.
    4. Evaluate the correlation between plasma clearance of iohexol obtained by the model and:
    A. The GFR estimated by CKD-EPI formula
    B. The GFR estimated by MDRD4 and MDRD6 formulas
    C. The GFR estimated by renal clearance of cystatine C (Uguen, Jezequel et al. 2016)
    5. Determine in the model of plasmatic clearance (cf. 3rd point in the secondary outcomes) the relevant covariates. Ascites, as well as Child Pugh and MELD scores, will be included as tested covariates.
    1. Calculer la clairance rénale de l’iohexol.
    2. Calculer la clairance plasmatique de l’iohexol.
    3. Construire un modèle de pharmacocinétique permettant d’estimer la clairance rénale à partir de la clairance plasmatique.
    4. Evaluer la concordance entre la clairance plasmatique de l’iohexol obtenue par le modèle et :
    - Le DFG estimé par la formule CKD-EPI
    - Le DFG estimé par les formules MDRD4 et MDRD6
    - Le DFG estimé par la clairance rénale de la cystatine C (Uguen, Jezequel et al. 2016)
    5. Déterminer dans le modèle de la clairance plasmatique (cf. objectif 3) les covariables pertinentes pouvant l’influencer. L’ascite ainsi que les stades Child et Meld feront partie des covariables testées.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with advanced liver disease, with potential indication for liver transplantation, with or without ascites:
    - No ascites: 3 patients.
    - Grade 1 (mild): ascites only detectable by ultrasound examination. 3 patients.
    - Grade 2 (moderate) and Grade 3 (wide): clinically significant ascites, causing moderate symmetrical distension of the abdomen, or causing severe abdominal distension. 3 patients.
    2-3-4. Moreover, patients will be over 18 years, affiliated to a social security scheme and give their informed consent.
    1. Patients suivis habituellement dans le service d’Hépato-Gastro-Entérologie et atteints de maladie hépatique avancée, avec indication potentielle de transplantation hépatique, avec ou sans ascite :
    - Sans ascite : 3 patients
    - Grade OMS 1 (minime) : ascite uniquement détectable par échographie : 3 patients.
    - Grade OMS 2 (modéré) ou grade OMS 3 (volumineux) : ascite cliniquement significative à l’origine d’une distension symétrique modérée de l'abdomen ou causant une distension abdominale marquée : 3 patients
    2. Patients âgés de 18 ans à 70 ans
    3. Affiliés à un régime de sécurité sociale
    4. Ayant donné leur consentement éclairé écrit
    E.4Principal exclusion criteria
    • Hypersensitivity to the active substance to iodinated contrast agents or any of the excipients listed in section Composition.
    • Antecedent of immediate major or cutaneous reaction, delayed to the injection of the iodinated contrast product (Omnipaque).
    • Patients with thyrotoxicosis.
    • Asthmatic patients.
    • Patients with severe cardiovascular disease.
    • Patients with central nervous system disorders, especially vascular.
    • Patients with pheochromocytoma.
    • Patients with myasthenia.
    • Patients with sickle cell disease.
    • Patients requiring anesthesia on the first day of sampling.
    • Patients requiring iodinated contrast injection during hospitalization and in the previous two weeks. Gadolinium injections are not contraindicated.
    • Patients under tutorship or curatorship or unable to give informed consent.
    • Patients already included in another interventional research protocol or in exclusion period.
    • Pregnant or lactating women
    1. Hypersensibilité à la substance active aux produits de contrastes iodés ou à l'un des excipients mentionnés à la rubrique Composition (p 68)
    2. Antécédent de réaction immédiate majeure ou cutanée retardée à l'injection du produit de contraste iodé (Omnipaque)
    3. Patients atteints de thyrotoxicose
    4. Patients asthmatiques
    5. Patient ayant des antécédents de dysthyroïdie
    6. Patients atteints de maladies cardiovasculaires sévères
    7. Patients atteints de troubles du système nerveux central notamment vasculaires
    8. Patients atteints de phéochromocytome
    9. Patients atteints de myasthénie
    10. Patients porteurs d’une drépanocytose
    11. Patients devant avoir une anesthésie le premier jour des prélèvements
    12. Patients devant avoir une injection de produit de contraste iodé pendant l’hospitalisation et dans les deux semaines précédentes. Les injections de gadolinium ne sont pas contre-indiquées
    13. Patients sous tutelle ou curatelle ou en incapacité de donner leur consentement éclairé
    14. Patients déjà inclus dans un autre protocole de recherche interventionnel ou en période d’exclusion
    15. Femmes enceintes ou allaitantes
    E.5 End points
    E.5.1Primary end point(s)
    Curves of plasma and urinary concentrations of iohexol as a function of time.
    Courbes de concentrations plasmatiques et urinaires de l’iohexol en fonction du temps.
    E.5.1.1Timepoint(s) of evaluation of this end point
    0 minute - 15 minutes - 30 minutes - 1 hour - 1,5 hours - 2 hours - 3 hours - 4 hours - 6 hours - 8 hours - 12 hours - 24 hours
    E.5.2Secondary end point(s)
    1. Renal clearance of iohexol obtained by non-compartmental analysis.
    2. Plasma clearance of iohexol obtained by non-compartmental analysis.
    3. The assessment of the performance of the model will be based on its ability to predict iohexol concentrations, expressed by the bias (%) and accuracy between urinary Predicted Plasma and Urinary and Plasma Concentrations Observed.
    4. Coefficients of linear correlations and scatter plots between plasma clearance of iohexol estimated by the model and GFR calculated by different methods. Bland Altman curves will also be drawn.
    5. 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 P <0.01 in the model. Search 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 24H,
    - 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
    1. Clairance rénale de l’iohexol obtenue par analyse non- compartimentale.
    2. Clairance plasmatique de l’iohexol obtenue par analyse non-compartimentale.
    3. L’évaluation de la performance du modèle sera basée sur sa capacité à prédire les concentrations d’iohexol, exprimée par le biais (%) et la précision (racine de la moyenne des biais au carré = RMSE) entre les concentrations urinaires et plasmatiques prédites et les concentrations urinaires et plasmatiques observées.
    4. Coefficients de corrélations linéaires et nuages de points entre la clairance plasmatique du iohexol estimée par le modèle et les DFG calculés par les différentes méthodes. Des courbes de Bland Altman seront aussi tracées.
    5. Evaluation des covariables par régression linéaire multiple et nuages de points (covariables continues) ou Mann Whitney et box plots (covariables catégorielles). Inclusion des covariables caractérisées par un P<0.01 dans le modèle. Recherche des covariables qui vont influencer la relation entre la clairance plasmatique et la clairance rénale :
    - grade d’intensité de l’ascite. 2 grades : minime (échographique) ou modéré et volumineux,
    - âge,
    - poids (du jour et H24),
    - sexe,
    - diurèse des 24H,
    - albumine,
    - natriurèse,
    - prise de diurétiques (nature et dose),
    - autres médicaments pouvant influencer le DFG,
    - stigmates biologiques d’insuffisance hépatique ou d’hypertension portale : bilirubine, albumine, INR, phosphatases, score de Child Pugh, score de MELD
    E.5.2.1Timepoint(s) of evaluation of this end point
    0 minute - 15 minutes - 30 minutes - 1 hour - 1,5 hours - 2 hours - 3 hours - 4 hours - 6 hours - 8 hours - 12 hours - 24 hours
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    Dernière visite du dernier patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 7
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-09-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-28
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