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    Summary
    EudraCT Number:2014-002544-40
    Sponsor's Protocol Code Number:5866
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-06-26
    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 number2014-002544-40
    A.3Full title of the trial
    THE TREATMENT OF HYPERTENSION ASSOCIATED WITH SEVERE PREECLAMPSIA.
    A RANDOMIZED CONTROLLED TRIAL OF URAPIDIL VERSUS NICARDIPINE.
    The URANIC trial.
    Traitement de l'hypertension au cours de la pré-éclampsie sévère. Essai randomisé contrôlé de l'urapidil vs nicardipine.
    L'essai URANIC.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    THE TREATMENT OF HYPERTENSION ASSOCIATED WITH SEVERE PREECLAMPSIA.
    A RANDOMIZED CONTROLLED TRIAL OF URAPIDIL VERSUS NICARDIPINE.
    The URANIC trial.
    A.3.2Name or abbreviated title of the trial where available
    URANIC
    A.4.1Sponsor's protocol code number5866
    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 SponsorHôpitaux 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 supportHôpitaux Universitaires de Strasbourg
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHôpitaux Universitaires de Strasbourg
    B.5.2Functional name of contact pointDRCI
    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 number003338811 52 66
    B.5.5Fax number003338811 52 40
    B.5.6E-maildrci@chru-strasbourg.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 Eupressyl
    D.2.1.1.2Name of the Marketing Authorisation holderLaboratoire Takeda France 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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country 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.3.1Product namenicardipine
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnicardipine
    D.3.9.1CAS number 54527-84-3
    D.3.9.3Other descriptive nameNICARDIPINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB03420MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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
    Hypertension associated with severe pre eclampsia
    Hypertension dans la pré-éclampsie sévère
    E.1.1.1Medical condition in easily understood language
    Hypertension associated with severe pre eclampsia
    Hypertension dans la pré-éclampsie sévère
    E.1.1.2Therapeutic area Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine if urapidil is non-inferior to nicardipine by a maximum margin of 10% on the success rate.
    Démontrer que l’urapidil est non inférieur à la nicardipine (seuil de non infériorité de 10% sur le taux de succès)
    E.2.2Secondary objectives of the trial
    - to compare the ease of use of urapidil with the ease of use of nicardipine,
    - to demonstrate better maternal tolerance of urapidil compared with nicardipine,
    - to look at the drug interactions between antihypertensive agents and other drugs used in the treatment of PE (anaesthetic agents, furosemide, magnesium sulfate),
    - to demonstrate the foetal and neonatal safety of urapidil after maternal administration,
    - to study the pharmacokinetics (PK) of urapidil after intravenous administration in course of the management of hypertension in PE (Transplacental transfer,Transfer to breast milk, Neonatal drug elimination in the moderately preterm baby (<33 WG).)
    Comparer la facilité d'utilisation de l'urapidil avec la facilité d'utilisation de la nicardipine,
    Démontrer une meilleure tolérance maternelle de l'urapidil par rapport à la nicardipine,
    Examiner les interactions médicamenteuses entre les agents antihypertenseurs et les autres médicaments utilisés dans le traitement de la PE (drogues d’anesthésie, furosémide, sulfate de magnésium),
    Démontrer l'innocuité fœtale et néonatale de l’urapidil après l'administration maternelle,
    Etudier la pharmacocinétique (PK) de l’urapidil après administration intraveineuse au cours de la gestion de l'hypertension dans la PE (transfert transplacentaire, transfert de lait maternel, élimination néonatale du médicament chez le prématuré (<33 SA).)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Adult patients
    •Singleton pregnancy
    •Patients with remaining hypertension despite an oral treatment for who an iv antihypertensive treatment is indicated

    •Patient with PE, as defined by :
    Systolic Blood Pressure (BP) ≥ 140 mmHg and/or Diastolic BP ≥ 90 mmHg, after the 20th week of amenorrhea, without chronic hypertension,
    AND
    Proteinuria > 300 mg.day-1 or > 2 crosses(++) on an urinary dipstick,

    OR

    •Patient with severe PIH, as defined by :
    Systolic BP ≥ 160mmHg and/or Diastolic BP ≥110mmHg, after the 20th week of amenorrhea, without chronic hypertension,

    •Written informed consent signed and dated by both investigator and patient
    •Patientes adultes
    •Grossesse unique
    •Patiente demeurant hypertendue malgré un traitement antihypertenseur oral et chez laquelle un traitement iv est indiqué

    •PE, définie par :
    Pression Artérielle Systolique (PAS) ≥ 140 mmHg et/ou Diastolique (PAD) ≥ 90 mmHg, après 20 semaines d’aménorrhée, sans antécédents d’hypertension chronique
    ET
    Protéinurie > 300 mg.j-1 ou > 2 croix(++) à la bandelette urinaire,

    OU

    •HTAG sévère, définie par :
    PAS ≥ 160mmHg et/ou PAD ≥110mmHg, après 20 semaines d’aménorrhée, sans antécédents d’hypertension chronique,

    •Consentement écrit signé par l’investigateur et la patiente
    E.4Principal exclusion criteria
    •Known allergy to the study drugs
    • Contra-indication to the study drugs :stenosis of the aortic isthmus, arteriovenous shunt, coarctation of the aorta, unstable angina, compensatory hypertension, myocardial infarction < 8 days.
    •Eclampsia
    •Person with difficulty understanding information
    •Person with diminished responsiblity,
    •Ongoing intravenous antihypertensive treatment,
    •No pressure cuff adapted to the morphology of the arms of the patients
    •Concomitant use of 5 phosphodiesterase inhibitors
    •Participation in a clinical trial within 6 months prior to inclusion
    •Allergies connues à une drogue de l'étude
    • Contre-indication à une drogue de l’étude: sténose de l’isthme aortique ou shunt artério-veineux, coarctation de l’aorte, angor instable, hypertension compensatoire, infarctus du myocarde < 8 jours
    •Eclampsie
    •Personne ayant des difficultés de compréhension
    •Incapables majeurs,
    •Traitement antihypertenseur iv en cours,
    •Brassard de sphygmomanomètre non adapté à la morphologie des bras,
    • Utilisation concomitante d'inhibiteurs de la phosphodiesterase 5
    •Participation à un essai clinique dans les 6 mois précédant l’inclusion.
    E.5 End points
    E.5.1Primary end point(s)
    Lowering the mean arterial blood pressure (MAP) between 100 and 120 mmHg.
    Diminution de la pression artérielle moyenne (PAM) entre 100 et 120 mmHg.
    E.5.1.1Timepoint(s) of evaluation of this end point
    2 hours following start treatment
    2 heures après le début du traitement
    E.5.2Secondary end point(s)
    Efficacy criteria: time needed to reach the therapeutic success, drug dose required to achieve therapeutic success, number of drug infusion rate adaptations, need for another antihypertensive agent, recurrence of hypertension after discontinuation of iv treatment, need for a therapeutic relay, evolution of systolic and diastolic blood pressure during antihypertensive therapy,

    Tolerance criteria: occurrence of maternal hypotension, occurrence of maternal tachycardia, occurrence of the maternal, foetal or neonatal side effects described for urapidil and nicardipine, need for treatment interruption due to side effects,

    Evolution of the pregnancy: coexistent treatment, complication of PE, obstetrical data,
    Drug interaction: signs of magnesium overdose, drug interaction with anaesthetic agents, furosemide,

    Anaesthetic data:
    type of labour analgesia and / or anaesthesia for Caesarean Section (spinal, epidural, systemic intravenous opioids, no anaesthesia)

    Neonatal data:
    Umbilical cord pH, Agar score, tachycardia, hypotension, need for intubation, duration of mechanical ventilation, side effects,

    Pharmacokinetic substudy:
    •Trans-placental transfer: At birth: determination of urapidil concentration in maternal blood and in the arterial and venous umbilical cord blood
    •Transfer in breast milk:
    After childbirth, daily determination of the urapidil and nicardipine concentration in systematic blood and breast milk samples during and up to 24 hours after stopping the administration of the antihypertensive drug,
    •Neonatal Elimination: Determinations of the urapidil concentration in the blood of moderately prematurate babies of mothers treated with urapidil (less than 33 WG) at ICU admission (H 2) and at 24 hours in systematic blood samples.
    Critères d'efficacité: temps nécessaire pour atteindre le succès thérapeutique, dose de médicament nécessaire pour atteindre le succès thérapeutique, nombre d'adaptations des taux de perfusion de médicaments, nécessité d'un autre agent antihypertenseur, récurrence de l'hypertension après l'arrêt du traitement iv, nécessité d'un relais thérapeutique, évolution de la pression artérielle systolique et diastolique au cours du traitement antihypertenseur,

    Critères de tolérance: survenue d'hypotension maternelle, survenue de tachycardie maternelle, survenue d’effets indésirables maternels, fœtaux ou néonataux décrits pour urapidil et nicardipine, nécessité d’interruption du traitement en raison d'effets secondaires,

    Evolution de la grossesse : traitement coexistant, complication de la PE, données obstétricales, interaction des médicaments: signes de surdosage de magnésium, interactions médicamenteuses avec les drogues d’anesthésie, le furosémide,

    Données d'anesthésie: type d’analgésie du travail et / ou anesthésie pour une césarienne (anesthésie générale, péridurale, opiacés par voie intraveineuse systémiques, sans anesthésie)

    Données néonatale: pH au cordon ombilical, score d’Apgar, tachycardie, hypotension, nécessité d'intubation, la durée de la ventilation mécanique, effets secondaires,

    Etude pharmacocinétique
    Transfert transplacentaire: A la naissance: détermination de la concentration d’urapidil dans le sang maternel et dans le sang artériel et veineux du cordon ombilical
    Transfert hémolacté: après accouchement, la détermination quotidienne de l'urapidil et de la nicardipine dans des échantillons de sang et de le lait maternel systématiques pendant et jusqu'à 24 heures après l'arrêt de l'administration de l'antihypertenseur,
    Elimination néonatale: déterminations de la concentration de l'urapidil dans le sang de prématuré nés de mères traitées par urapidil (moins de 33 SA) à l'admission en USI néonataux (H 2) et à 24 heures à partir d’échantillons de sang systématiques.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy criteria : end of the treatment

    Tolerance criteria : until the end of the treatment

    Evolution of the pregnancy : until delivery

    Data anesthesia : at delivery

    Neonatal data: at birth

    Pharmacokinetic substudy:
    •Trans-placental transfer: At birth
    Transfer in breast milk: after childbirth, daily (during the normal blood tests) during the treatment and up to 24 hours after stopping

    Neonatal Elimination: at 2 hours and 24 hours of life
    Critères d'efficacité: fin du traitement

    Critères de tolérance : tout au long du traitement

    Evolution de la grossesse : jusquà l'accouchement

    Données d'anesthésie : à l'accouchement

    Données néonatales : à la naissance

    Etude pharmacocinétique
    Transfert transplacentaire: à la naissance
    Transfert hémolacté: après l'accouchement quotidiennement (au cours des bilans habituels) pendant la durée du traitement et jusqu'à 24h après son arrêt

    Elimination néonatale: à H2 et H24
    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 Yes
    E.6.5Efficacy Yes
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    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) Yes
    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 Yes
    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 sujet
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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: 366
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    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 Yes
    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 state366
    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)
    If the antihypertensive therapy needs to be continued for more than 7 days, the patients are treated with intravenous or oral nicardipine according to the practitioner’s judgment

    If the treatment did not succeed (BP > 120mmHg after 2 hours) : each investigator chooses the treatment needed (nicardipine or labetalol iv relay)
    Si le traitement anti-hypertenseur doit être continué pour plus de 7 jours, les patientes seront traitées avec de la nicardipine en intraveineuse ou per os selon le jugement du médecin traitant.

    Si le traitement est un échec (PAM > 120 mmHg après 2h), chaque investigateur choisit le traitement adapté (relai iv nicardipine ou labetalol)
    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 Decision2014-09-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-29
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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