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    Summary
    EudraCT Number:2014-005033-31
    Sponsor's Protocol Code Number:SIK-FR14-1
    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:2015-02-20
    Trial 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 number2014-005033-31
    A.3Full title of the trial
    Evaluation of the impact of renal function on the pharmacokinetics of hydroxyurea (Siklos®) in patients with sickle cell disease with normal renal function, with hyperfiltration, or with renal failure.
    Evaluation de l’impact de la fonction rénale sur la pharmacocinétique de l’hydroxyurée (SIKLOS®) chez les patients drépanocytaires normo-rénaux, hyperfiltrants et insuffisants rénaux (DARH).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of the impact of renal function on the pharmacokinetics of hydroxyurea (Siklos®) in patients with sickle cell disease with normal renal function, with hyperfiltration, or with renal failure. DARH study
    Evaluation de l’impact de la fonction rénale sur la pharmacocinétique de l’hydroxyurée (SIKLOS®) chez les patients drépanocytaires normo-rénaux, hyperfiltrants et insuffisants rénaux. Etude DARH.
    A.3.2Name or abbreviated title of the trial where available
    DARH
    DARH
    A.4.1Sponsor's protocol code numberSIK-FR14-1
    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 SponsorAddmedica S.A.S
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAddmedica S.A.S
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAddmedica S.A.S
    B.5.2Functional name of contact pointMedical director
    B.5.3 Address:
    B.5.3.1Street Address101 rue Saint-Lazare
    B.5.3.2Town/ cityParis
    B.5.3.3Post codeF-75009
    B.5.3.4CountryFrance
    B.5.4Telephone number0033172690186
    B.5.5Fax number0033173729413
    B.5.6E-mailcorinne.duguet@addmedica.com
    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 SIKLOS
    D.2.1.1.2Name of the Marketing Authorisation holderAddmedica S.A.S.
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/03/154
    D.3 Description of the IMP
    D.3.1Product nameSiklos
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral 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
    Siklos is indicated for the prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in adults, adolescents and children older than 2 years suffering from symptomatic sickle cell syndrome.
    Siklos est indiqué dans la prévention des crises vaso-occlusives douloureuses récurrentes y compris celle du syndrome thoracique aigu chez l’adulte, l’adolescent et l'enfant âgé de plus de 2 ans souffrant de drépanocytose symptomatique
    E.1.1.1Medical condition in easily understood language
    Siklos is indicated for the prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in patients suffering from symptomatic sickle cell syndrome.
    Siklos est indiqué dans la prévention des crises vaso-occlusives douloureuses récurrentes y compris celle du syndrome thoracique aigu pour les patients souffrant de drépanocytose symptomatique.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10040643
    E.1.2Term Sickle cell crisis
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Comparison of the different pharmacokynetics parameters of hydroxyurea in sickle-cell patients with a renal condition (glomerular hyperfiltration and moderate renal) to those presenting a normal renal function.
    comparer les paramètres pharmacocinétiques de l’hydroxyurée des patients drépanocytaires normo-rénaux à ceux des patients présentant une hyperfiltration glomérulaire ou une insuffisance rénale modérée.
    E.2.2Secondary objectives of the trial
    a. Development of a pharmacokinetic model to measure the variability of pharmacokinetic parameters in the study population.
    b. Definition of the relevant covariates: demographic, biologic, therapeutic (treatment with angiotensin-converting-enzyme inhibitors) explaining the pharmacokinetic variability of hydroxyurea for each study group.
    c. Definition of a model including the individual pharmacokinetic parameters allowing to adapt the posology of hydroxyurea according to the renal function.
    a. Développer un modèle pharmacocinétique permettant de mesurer les
    variabilités des paramètres pharmacocinétiques dans la population
    étudiée.
    b. Définir les covariables pertinentes : démographiques, biologiques,
    thérapeutiques (traitement par inhibiteur de l’enzyme de conversion
    [IEC]) expliquant les variabilités pharmacocinétiques de l’hydroxyurée
    pour chaque groupe étudié.
    c. Définir un modèle incluant les paramètres pharmacocinétiques
    individuels qui permettrait d’adapter les posologies de l’hydroxyurée
    selon la fonction rénale.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a. Age ≥ 18 years.
    b. Masculin or feminin sex.
    c. Drepanocytose (SS or S-β0thal) confirmed by hemoglobine electrophorese and genotype of desosxyribonucleic acid (DNA).
    d. adhere to national insurance program.
    e. Have given their free consent after having been informed of the goals, proceedings, and potential risks .
    these criteria will be applied to all 3 groups. The group the subjects will belong to will be defined by the glomerular filtration rate (GFR) estimated using Chronic Kidney Disease EPIdemiology (CKD EPI) cformular without etnic criteria.
    Underhydroxyurea (Siklos®) treatment .with stable psology for at least 1 week± 2 jours before inclusion and taken every morning at 9h ± 15 minutes.
    a. Age ≥ 18 ans.
    b. Sexe masculin ou féminin.
    c. Drépanocytose (SS ou S-β0thal) confirmée par l’électrophorèse de
    l’hémoglobine et le génotypage par l’analyse de l’acide
    désoxyribonucléique (ADN).
    d. Affiliation à un régime de sécurité sociale.
    e. Ayant donné librement leur consentement écrit après avoir été informés
    du but, du déroulement et des risques potentiels encourus.
    Ces critères seront appliqués aux 3 groupes de patients drépanocytaires selon
    le stade de la fonction rénale défini par le débit de filtration glomérulaire
    (DFG) estimé par la formule du Chronic Kidney Disease EPIdemiology
    (CKD EPI) collaboration sans critère ethnique.
    Sous traitement par l’hydroxyurée (Siklos®) avec une posologie stable
    depuis au moins une semaine ± 2 jours avant l’inclusion dans l’étude et
    prise le matin à 9h ± 15 minutes.
    E.4Principal exclusion criteria
    a. Consent refusal
    b. Non observant patient.
    c. Having suffered from a vaso-occlusive crisis during the month before inclusion.
    d. having undergone tranfusional exchange withiin the 3 months prio to inclusion.
    e. Patients participating to anothe study or in exclusion period from a previous study.
    f. Patients under diuretics.
    g. Patients suffering from an intercurrent illness, particularly inflammatory, non resolved since at least 1 month.
    h. Patiente pregnat or breast-feeding.
    i. Patients with no or restraint freedom.
    j. Patients unable to understand the goal of the study therefore not able to give their consent.
    k. if suffering from severe hepatic failure.
    l. in case of severe hepatic failure (creatinine clairance < 30
    mL/min).
    m.Patients presenting toxic signs of myelosuppression.
    a. Refus de consentement.
    b. Patients non observants.
    c. Survenue d’une crise vaso-occlusive au cours du mois précédant
    l’inclusion dans l’étude.
    d. Patients ayant eu un échange transfusionnel durant les 3 derniers mois
    avant l’inclusion dans l’étude.
    e. Patients participant à un autre essai clinique ou en période d’exclusion
    d’un essai clinique précédent.
    f. Patients traités par un diurétique.
    g. Patients ayant une affection intercurrente, en particulier inflammatoire,
    non résolue depuis moins d’un mois.
    h. Patientes enceintes ou allaitantes.
    i. Patients privés de liberté ou sous tutelle.
    j. Patients incapables de comprendre le but et les conditions de déroulement
    de l’étude, incapables de donner leur consentement.
    k. En cas d’insuffisance hépatique sévère.
    l. En cas d’insuffisance rénale sévère (clairance de la créatinine < 30
    mL/min).
    m.Patients présentant des signes toxiques de myélosuppression.
    E.5 End points
    E.5.1Primary end point(s)
    comparison of the below pharmacokynetics parametres amongst the 3 studied groups (3 different renal conditions) with a P value <0.05 :
    •Plasmatic data: Cmax, Cmin, Tmax, AUCO-24, T1/2, CI tot and distribution volumen.
    •Urine data: hydroxyurea urine fractions, renal CI.
    Comparaison des données pharmacocinétiques ci-dessous entre les 3
    groupes étudiés avec un critère de significativité statistique P value <0.05 :
    • Données plasmatiques : concentration maximale (Cmax), concentration
    minimale (Cmin), temps d’atteinte de la concentration maximale
    (Tmax), aire sous la courbe (AUC0-24), demi-vie d’élimination (T½),
    clairance totale (Cl tot) et volume de distribution.
    • Données urinaires : fractions urinaires de l’hydroxyurée, clairance rénale (Cl
    rénale).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Biological blood tests: %HbF, hemogram, reticulocytaire formulae, urea, creatinine, ALAT, ASAT, LDH, total bilirubine, akaline reserve at T-1h
    Hydroxyurea level at T0h
    Hydroxyurea pharmacokynetic: T0, 0.75h, 1.5h, 3h, 4h, 6h, 7.5h, T24
    urine sampling Hydroxyurea pharmacokynetic and diurese: T0-4h, 4-7.5h + T24
    Examens biologiques sanguins: %HbF, hémogramme, formule réticulocytaire, urée, créatinine, alanine aminotransférase (ALAT), aspartate aminotransférase (ASAT), lactate déshydrogénase (LDH), bilirubines totales, réserves alcalines (3 prélèvements sanguins de 4 mL chacun): T-1h
    Prise de l’hydroxyurée: T0h
    Prélèvements sanguins pour la pharmacocinétique de l’hydroxyurée (5 mL par point de cinétique): T0, 0.75h, 1.5h, 3h, 4h, 6h, 7.5h
    Recueils d’urines pour la pharmacocinétique de l’hydroxyurée et diurèse: T0-4h, 4-7.5h
    Prélèvement sanguin pour la pharmacocinétique de l’hydroxyurée (5 mL), Recueils d’urines pour la pharmacocinétique de l’hydroxyurée et diurèse: T24h
    E.5.2Secondary end point(s)
    a.Pharmacokynetic Model selection criteria: likelihood test and Objective Function minimisation (OF) between the reduced and final model: if ΔOF ≥ 3.84 complete model superior to reduced model (P<0.05).
    b. Covariables selection criteria: likelihood test and Objective Function minimisation (OF) between the reduced and final model: if ΔOF ≥ 3.84 complete model superior to reduced model (P<0.05).
    c. Model validation criteria using Bland and Altman test by evaluatinf the agreement between calculated parametres using the model and the observed ones: data cloud distribution between superior limit agreement [biais+ (standard deviation*1.96)] and inferior limit agreement [biais- (standard deviation*1.96)]
    d. Pharmacokynetic parametres variations of hydroxyurea in patients treated by Ramipril during 2 periods:
    period 1: under ramipril
    period 2: after 30 days wash-out of any ARA II including ramipril
    a. Critère de sélection du modèle pharmacocinétique de population: test du
    rapport de vraisemblance minimisation de la fonction objective (OF)
    entre le modèle réduit et le modèle final : Si ΔOF ≥ 3.84, supériorité du
    modèle complet vs. modèle réduit (P<0.05)
    b. Critère de sélection des covariables : test du rapport de vraisemblance :
    minimisation de l’OF entre le modèle réduit et le modèle final : Si ΔOF
    ≥ 3.84, supériorité du modèle complet vs. modèle réduit (P<0.05)
    c. Critère de validation du modèle par le test de Bland et Altman par
    l’évaluation de la concordance entre les paramètres calculés par le
    modèle et les paramètres observés : répartition des nuages de points
    entre la limite de concordance supérieure [error+ (écart-type*1.96)] et la
    limite de concordance inférieure [error-(écart-type*1.96)]
    d. Variation des paramètres pharmacocinétiques de l’hydroxyurée chez les
    patients traités par le ramipril, un inhibiteur de l’IEC entre deux
    périodes :
    · Période 1 : sous ramipril
    · Période 2 : après 30 jours de wash-out de tout IEC (dont
    ramipril) et tout ARA II
    E.5.2.1Timepoint(s) of evaluation of this end point
    T24h
    T24h
    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 Yes
    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.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    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
    Dernier dosage de la 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 months8
    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: 42
    F.1.3Elderly (>=65 years) No
    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 state42
    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.
    Aucun.
    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 Decision2015-02-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-02-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-11-29
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