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    Summary
    EudraCT Number:2021-002094-26
    Sponsor's Protocol Code Number:8100
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2022-04-19
    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 number2021-002094-26
    A.3Full title of the trial
    Optimization of the management of drepanocytosis patients
    treated with hydroxyurea: Interest of the pharmacological therapeutic follow-up
    Optimisation de la prise en charge des patients drépanocytaires
    traités par hydroxyurée : Intérêt du suivi thérapeutique pharmacologique
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Optimization of the management of drepanocytosis patients
    treated with hydroxyurea: Interest of the pharmacological therapeutic follow-up
    Optimisation de la prise en charge des patients drépanocytaires
    traités par hydroxyurée : Intérêt du suivi thérapeutique pharmacologique
    A.3.2Name or abbreviated title of the trial where available
    OPTIMDREP
    OPTIMDREP
    A.4.1Sponsor's protocol code number8100
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLes Hôpitaux Universitaires de Strasbourg
    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 supportLes Hôpitaux Universitaires de Strasbourg
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLes Hôpitaux Universitaires de Strasbourg
    B.5.2Functional name of contact pointSarah HUSTACHE
    B.5.3 Address:
    B.5.3.1Street Address1, place de l'hôpital
    B.5.3.2Town/ cityStrasbourg
    B.5.3.3Post code67091
    B.5.3.4CountryFrance
    B.5.4Telephone number3388115266
    B.5.5Fax number33 88115494
    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.2.5The 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.3.1Product nameHydroxycarbamide
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHYDROXYCARBAMIDE
    D.3.9.1CAS number 21520-79-6
    D.3.9.4EV Substance CodeSUB08076MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number100 to 1000
    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
    Drepanocytosis
    Drépanocytose
    E.1.1.1Medical condition in easily understood language
    Drepanocytosis
    Drépanocytose
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10010331
    E.1.2Term Congenital, familial and genetic disorders
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10051835
    E.1.2Term Drepanocytosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Compare the time to reach DMT in 2 groups of patients each with a different methodology of therapeutic follow-up
    Comparer le délai d’atteinte de la DMT dans 2 groupes de patients ayant chacun une méthodologie différente de suivi thérapeutique
    E.2.2Secondary objectives of the trial
    1) Evaluate the clinical effectiveness of HU treatment according to management strategy
    2) Evaluate the toxicity of HU treatment according to the management strategy
    3) Conduct a pharmacokinetic/pharmacodynamic study of hydroxyurea in a paediatric and adult population
    4) Establish a population pharmacokinetics database and identify the parameters involved in the pharmacokinetic variability of hu to better predict individual dose adjustment from our population study.
    5) Confirm the merits of reducing the number of samples in children, but also in adults, by demonstrating that a single sample at time (T = 2 hours) is sufficient to predict exposure to the drug and allow dosage adjustment.
    1) Evaluer l’efficacité clinique du traitement par HU selon la stratégie de prise en charge
    2) Evaluer la toxicité du traitement par HU selon la stratégie de prise en charge
    3) Réaliser une étude de pharmacocinétique/pharmacodynamie de l’hydroxyurée dans une population pédiatrique et adulte
    4) Constituer une base de données de pharmacocinétique de population et identifier les paramètres impliqués dans la variabilité pharmacocinétique de l’HU permettant de mieux prédire l’adaptation posologique individuelle à partir de notre étude de population.
    5) Confirmer le bienfondé de réduire le nombre de prélèvements chez les enfants, mais aussi chez les adultes, en démontrant qu’un seul prélèvement au temps (T=2 heures) est suffisant pour prédire l’exposition au médicament et permettre une adaptation posologique.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Subject of age between 2 and 35 years.
    - Sickle cell genotype: HbSS
    - Subject who has been hospitalized for CVO in the last 3 months in whom hu treatment is to be initiated and / or whose treatment is not balanced or less than 30 mg / kg regardless of the age of treatment
    - For a woman of childbearing age:
    o Negative blood pregnancy test at inclusion visit
    o Patient accepting highly effective contraception for the duration of participation in the study and 182 days after discontinuation of the study or treatment for a woman. The contraceptives considered highly effective are:
    ▪ Combined hormonal contraception (containing estrogen and progesterone) associated with ovulation inhibition: oral, intravaginal, transdermal
    ▪ Hormonal contraception progesterone alone associated with ovulation inhibition: oral, injectable, implantable
    ▪ intrauterine device
    ▪ intrauterine device with hormone release
    ▪ tubal ligation
    ▪ partner's vasectomy
    ▪ sexual abstinence
    - For men of childbearing age: patient accepting effective contraception throughout the study and for 92 days after stopping the study or treatment, use of condoms in the included patient as well as taking contraception by the partner of childbearing age.
    - Initiation of HU treatment in a patient requiring therapeutic intensification in the context of sickle cell disease
    - Hospitalized patient (e.g. vaso-occlusive crisis) and / or whose treatment with HU is unbalanced (DMT not reached)
    - Subject affiliated to a social protection scheme for health insurance or beneficiary
    - Subject who has been informed of the results of the prior medical examination, and/or whose holder(s) of parental authority has been informed(s)
    - Subject able to understand the objectives and risks related to the research and to give dated and signed informed consent
    - Informed consent signed as the case may be, by:
    o the patient and/or
    o the holder(s) of parental authority and the minor subject if he is capable of discernment,



    - Sujet d’âge compris entre 2 et 35 ans.
    - Génotype drépanocytaire : HbSS
    - Sujet ayant été hospitalisé pour CVO dans les 3 derniers mois chez qui le traitement par HU est à initier et/ou dont le traitement n’est pas équilibré ou inférieur à 30 mg/kg indépendamment de l’ancienneté du traitement
    - Pour une femme en âge de procréer :
    o Test de grossesse sanguin négatif à la visite d’inclusion
    o Patiente acceptant une contraception hautement efficace pendant toute la durée de participation à l’étude et 182 jours après l’arrêt de l’étude ou du traitement pour une femme. Les contraceptions considérées comme hautement efficace sont :
    ▪ Contraception hormonale combinée (contenant oestrogène et progestérone) associée à une inhibition de l’ovulation : orale, intravaginale, transdermique
    ▪ Contraception hormonale progestérone seule associée à une inhibition de l’ovulation : orale, injectable, implantable
    ▪ dispositif intra-utérin
    ▪ dispositif intra-utérin avec libération d’hormone
    ▪ ligature des trompes
    ▪ vasectomie du partenaire
    ▪ abstinence sexuelle
    - Pour les hommes en âge de procréer : patient acceptant une contraception efficace pendant toute l’étude et pendant 92 jours après l’arrêt de l’étude ou du traitement,.utilisation du préservatif chez le patient inclus ainsi que prise d’une contraception par la partenaire en âge de procréer.
    - Initiation d’un traitement par HU chez un patient nécessitant une intensification thérapeutique dans le cadre d’une drépanocytose
    - Patient hospitalisé (ex : crise vaso-occlusive) et/ou dont le traitement par HU est non équilibré (DMT non atteinte)
    - Sujet affilié à un régime de protection sociale d’assurance maladie ou ayant-droit
    - Sujet ayant été informé des résultats de la visite médicale préalable, et/ou dont le(s) titulaire(s) de l’autorité parentale a (ont) été informé(s)
    - Sujet apte à comprendre les objectifs et les risques liés à la recherche et à donner un consentement éclairé daté et signé
    - Consentement éclairé signé selon le cas, par :
    o le patient et/ou
    o le(s) titulaire(s) de l’autorité parentale et le sujet mineur s’il est capable de discernement,





    E.4Principal exclusion criteria
    - Patient treated with HU who has reached DMT (hematological criteria) or who does not have therapeutic ineffectiveness or hydroxyurea dosage > 350 mg / kg / day.
    - Refusal to agree to use a highly effective contraceptive method as defined during a HU treatment and during the 182 days for women and 92 days for men following this treatment (fertile patients only).
    - Patient with a parental project within 18 months
    - Hypersensitivity to the active substance or to any of the excipients of the drug.
    - Severe hepatic impairment.
    - Severe renal failure.
    - Toxic signs of myelosuppression
    o Neutrophils < 1,500/mm3
    o Platelets < 80,000/mm3
    o Hemoglobin < 4.5 g/dL
    o Reticulocytes < 80,000/mm3 if the haemoglobin concentration is < 9 g/dL
    - Patient who received a transfusion, transfusion exchanges or administration of erythropoietin within 3 months before inclusion
    - Subject in period of exclusion (determined by a previous or ongoing study)
    - Inability to give informed information about (subject in emergency situation)
    - Concomitant inclusion in another drug study
    - Subject under safeguard of justice
    - Impossibility for the subject to submit to the medical follow-up of the trial for geographical, social or psychological reasons
    - Subject under guardianship or curatorship
    - Pregnancy or breastfeeding in progress for teenagers or adults
    - Patient traité par HU ayant atteint la DMT (sur les critères hématologiques) ou ne présentant pas d’inefficacité thérapeutique ou posologie d’hydroxyurée > 350 mg/kg/jour.
    - Refus d'accepter d'utiliser une méthode contraceptive hautement efficace telle que définie lors d'un traitement par HU et pendant les 182 jours pour les femmes et 92 jours pour les hommes suivants ce traitement (patients fertiles uniquement).
    - Patient(e) ayant un projet parental dans les 18 mois
    - Hypersensibilité à la substance active ou à l’un des excipients du médicament.
    - Insuffisance hépatique sévère.
    - Insuffisance rénale sévère.
    - Signes toxiques de myélosuppression
    o Neutrophiles < 1 500/mm3
    o Plaquettes < 80 000/mm3
    o Hémoglobine < 4,5 g/dL
    o Réticulocytes < 80 000/mm3 si la concentration en hémoglobine est < 9 g/dL
    - Patient ayant reçu une transfusion, des échanges transfusionnels ou une administration d’érythropoïétine dans les 3 mois avant inclusion
    - Sujet en période d’exclusion (déterminée par une étude précédente ou en cours)
    - Impossibilité de donner au sujet des informations éclairées (sujet en situation d’urgence)
    - Inclusion concomitante dans une autre étude de médicament
    - Sujet sous sauvegarde de justice
    - Impossibilité pour le sujet de se soumettre au suivi médical de l’essai pour des raisons géographiques, sociales ou psychiques
    - Sujet sous tutelle ou sous curatelle
    - Grossesse ou allaitement en cours pour les adolescentes ou personnes majeures
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects with a time to reach LMA of less than 9 months.
    Proportion de sujets ayant un délai pour atteindre la DMT inférieur à 9 mois.
    E.5.1.1Timepoint(s) of evaluation of this end point
    9 months
    9 mois
    E.5.2Secondary end point(s)
    1. Clinical parameters of efficacy in both arms:
    has. Number of vaso-occlusive seizures
    b. Number of complications related to sickle cell disease and/or hydroxyurea
    c. Number of hospitalizations
    d. Time elapsed before the need for transfusion
    e. Percentage of HbF
    2. Biological parameters of toxicity in both arms:
    has. Complete blood count, reticulocytes, ferritin
    b. Renal function (glomerular filtration rate estimated by cystatin C, plasma creatinine and urea)
    c. Liver function (AST, ALT, total and conjugated bilirubin).
    3. Non-compliance parameters:
    has. Mean blood cell volume (MCV)
    b. Percentage of HbF
    4. Population pharmacokinetic parameters of the 2 arms:
    a. AUC
    b. Clearance and volume of distribution of the drug.
    Pharmacokinetic analysis:
    has. Pharmacokinetic modeling of the population and identification of parameters involved in the inter- and intra-individual variability of the pharmacokinetics of the HU and allowing to better predict the individual dosage adaptation from our population study:
    i. Renal function
    ii. Age
    iii. Weight
    iv. Body surface
    v. % HbF
    b.Correlation between the concentrations obtained at the different sampling times and the AUC
    1. Paramètres cliniques de l’efficacité dans les deux bras :
    a. Nombre de crises vaso-occlusives
    b. Nombre de complications en lien avec la drépanocytose et/ou à la prise de hydroxyurée
    c. Nombre d’hospitalisations
    d. Délai écoulé avant la nécessité de recourir à une transfusion
    e. Pourcentage d’HbF
    2. Paramètres biologiques de la toxicité dans les deux bras :
    a. Numération formule sanguine, réticulocytes, ferritine
    b. Fonction rénale (débit de filtration glomérulaire estimé par la cystatine C, créatinine plasmatique et urée)
    c. Fonction hépatique (ASAT, ALAT, bilirubine totale et conjuguée).
    3. Paramètres de non observance :
    a. Volume globulaire moyen (VGM)
    b. Pourcentage d’HbF
    4. Paramètres pharmacocinétiques de population des 2 bras :
    a. AUC
    b. Clairance et volume de distribution du médicament.
    Analyse pharmacocinétique :
    a. Modélisation pharmacocinétique de la population et identification de paramètres impliqués dans la variabilité inter- et intra-individuelle de la pharmacocinétique de l’HU et permettant de mieux prédire l’adaptation posologique individuelle à partir de notre étude de population :
    i. Fonction rénale
    ii. Age
    iii. Poids
    iv. Surface corporelle
    v. % HbF
    b.Corrélation entre les concentrations obtenues aux différents temps de prélèvement et l’AUC
    E.5.2.1Timepoint(s) of evaluation of this end point
    3 months, 3 months + 15 days, 6 months, 6 months + 15 days, 9 months, 9 months + 15 days, 12 months, 12 months + 15 days, 15 months
    3mois, 3 mois + 15 jours, 6 mois, 6 mois + 15 jours, 12 mois, 12 mois + 15 jours, 15 mois
    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 Yes
    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 trial2
    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
    DVDP
    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 months18
    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 Yes
    F.1.1Number of subjects for this age range: 30
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 14
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 14
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2
    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 state30
    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)
    patients will be cared for according to the results of the study
    les patients seront pris en charge selon les résultats de l'étude
    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 Decision2022-07-07
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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