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    Summary
    EudraCT Number:2017-003321-14
    Sponsor's Protocol Code Number:P160942J
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-03-21
    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 number2017-003321-14
    A.3Full title of the trial
    Prevention of DElirium with MELatonine in intensive care unit : prospective, multicenter, randomized, double-blind, placebo, multi-arm, multi-stage trial.
    Prévention du DElirium en réanimation par la MELatonine: étude prospective, multicentrique, randomisée, en double aveugle, contre placebo, multi-bras, multi-stades.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Prevention of DElirium with MELatonine in intensive care unit
    Prévention du delirium avec la mélatonine en réanimation
    A.3.2Name or abbreviated title of the trial where available
    DEMEL
    A.4.1Sponsor's protocol code numberP160942J
    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 SponsorASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    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 supportDGOS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    B.5.2Functional name of contact pointDRCI Hôpital St Louis
    B.5.3 Address:
    B.5.3.1Street Address 1 av. Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.6E-mailfrance.guyot@aphp.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 No
    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 nameMélatonine 0.3 mg per day
    D.3.4Pharmaceutical form Oral solution
    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 INNMelatonine
    D.3.9.1CAS number 73-31-4
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.02
    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 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 No
    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 nameMélatonine 3 mg per day
    D.3.4Pharmaceutical form Oral solution
    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 INNMelatonine
    D.3.9.1CAS number 73-31-4
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.2
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    patients in intensive care unit with invasive mechanical ventilation
    patients de réanimation sous ventilation mécanique invasive
    E.1.1.1Medical condition in easily understood language
    patients in intensive care unit with invasive mechanical ventilation
    Patients de réanimation sous ventilation mécanique invasive
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012218
    E.1.2Term Delirium
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the pharmacokinetics and efficacy of melatonin in the prevention of delirium in ventilated patients in the intensive care unit.
    L'objectif principal est d'évaluer la pharmacocinétique et l'efficacité de la mélatonine dans la prévention du délirium chez les patients ventilés de réanimation.
    E.2.2Secondary objectives of the trial
    The secondary objectives are to evaluate the effect of melatonin on morbidity and mortality (duration of ventilation, length of stay, mortality) and sleep, as well as its tolerance
    Les objectifs secondaires sont d'évaluer l'effet de la mélatonine sur la morbi-mortalité (durée de ventilation, durée de séjour, mortalité) et le sommeil, ainsi que sa tolérance.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age > = 18 years
    - Patient with invasive mechanical ventilation
    - Anticipated stay in intensive care unit of at least 48 hours
    - Informed consent signed by the patient or a trusted person / family member or lack of consent in the event of a life-threatening emergency
    - Age >=18 ans
    - Patient sous ventilation mécanique invasive
    - Durée anticipée de séjour en réanimation d'au moins 48 heures
    - Consentement éclairé signé par le patient ou une personne de confiance/membre de la famille ou absence de consentement en cas de situation d'urgence vitale
    E.4Principal exclusion criteria
    - Admission in the intensive care unit for more than 48 hours
    - Pregnancy or breastfeeding
    - No understanding of the French language, deafness
    - Dementia (Mini Mental State <20) or known chronic psychosis
    - Delirium (positive CAM-ICU score) before or at the time of randomization
    - Alcohol withdrawal syndrome with Cushman score >=5 before or at the time of randomization
    - Inability to use the enteral route, food intolerance with vomiting
    - Severe hepatic insufficiency (prothrombin level <30%)
    - Ongoing treatment with melatonin or drugs that interact with or modify its metabolism (fluvoxamine, 5- or 8-methoxypsoralen, estrogen, cimetidine, carbamazepine, rifampicin)
    - Dying patient
    - Patient under tutorship or curatorship
    - Patient deprived of liberty by judicial or administrative decision
    - Patient not affiliated to a social security scheme and not a beneficiary of such a scheme
    - Patient participating in another interventional clinical study with melatonin and / or for whom delirium is the primary endpoint.
    - Allergy known to melatonin
    - Patient admitted to intensive care for a cardiorespiratory arrest, stroke, head trauma, neurosurgery.
    - Admission en réanimation depuis plus de 48 heures
    - Grossesse ou allaitement
    - Non compréhension de la langue française, surdité
    - Démence (Mini Mental State <20) ou psychose chronique connue
    - Délirium (score CAM-ICU positif) avant ou au moment de la randomisation
    - Syndrome de sevrage alcoolique avec score de Cushman >=5 avant ou au moment de la randomisation
    - Impossibilité d'utiliser la voie entérale, intolérance alimentaire avec vomissements
    - Insuffisance hépatique sévère (taux de prothrombine <30%)
    - Traitement en cours par melatonine ou médicaments interagissant ou modifiant son métabolisme (fluvoxamine, 5- ou 8-methoxypsoralène, estrogène, cimétidine, carbamazépine, rifampicine)
    - Patient moribond
    - Patient sous tutelle ou curatelle
    - Patient privé de liberté par décision judiciaire ou administrative
    - Patient non affilié à un régime de sécurité sociale et non bénéficiaire d'un tel régime
    - Patient participant à une autre étude clinique interventionnelle portant sur la mélatonine et/ou pour laquelle le délirium est le critère principal de jugement.
    - Allergie connue à la mélatonine
    - Patient admis en réanimation pour un arrêt cardio-respiratoire, un accident vasculaire cérébral, un traumatisme crânien, une neurochirurgie.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of efficacy (Phase 2) is the proportion of patients who experienced delirium between randomization and D14 (or death or intensive care unit exit if they occur before D14).
    The primary intermediate endpoint ("activity") for the selection of the most promising experimental arm in the interim analysis is the percentage of patients with an "optimal" pharmacokinetic profile of melatonin 48 hours after initiation of study treatment.

    Le critère d'évaluation principal final " efficacité " (phase 2) est la proportion de patients ayant présenté un delirium entre la randomisation et J14 (ou le décès ou la sortie de réanimation si ces derniers ont lieu avant J14).
    Le critère d'évaluation principal intermédiaire (" activité ") pour la sélection du bras expérimental le plus prometteur lors de l'analyse intermédiaire est le pourcentage de patients avec un profil pharmacocinétique " optimal " de mélatonine 48 heures après l'initiation du traitement de l'étude.
    E.5.1.1Timepoint(s) of evaluation of this end point
    14 days
    14 jours
    E.5.2Secondary end point(s)
    - Number of days living without delirium or coma between randomization and J14
    - Proportion of days with delirium in intensive care between randomisation and J14
    - Duration of mechanical ventilation, number of days living without ventilation between randomisation and J28
    - Use of sedative, analgesic and psychotropic treatments between randomization and J14 (or death or intensive care unit exit if they take place before D14).
    - Clinical evaluation of sleep by the nurse in charge of the patient and the patient himself (if normal consciousness) using the Richards-Campbell score
    - Length of stay in intensive care unit and hospital
    - Mortality at D28, in intensive care and at the hospital
    - Quality of life, anxiety depression, addiction and post traumatic stress at J90
    - Nombre de jours vivant sans delirium ni coma entre la randomisation et J14
    - Proportion de jours avec délirium en réanimation entre la randomisation et J14
    - Durée de ventilation mécanique, nombre de jours vivant sans ventilation entre la randomisation et J28
    - Utilisation des traitements sédatifs, analgésiques et psychotropes entre la randomisation et J14 (ou le décès ou la sortie de réanimation si ces derniers ont lieu avant J14).
    - Evaluation clinique du sommeil par l'infirmière en charge du patient et le patient lui-même (si conscience normale) à l'aide du score de Richards-Campbell
    - Durée de séjour en réanimation et à l'hôpital
    - Mortalité à J28, en réanimation et à l'hôpital
    - La qualité de vie, l'anxiété dépression, la dépendance et le stress post traumatique à J90
    E.5.2.1Timepoint(s) of evaluation of this end point
    90 days
    90 jours
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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) Yes
    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 No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned19
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    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: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    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 Yes
    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 state355
    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 Decision2018-05-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-03
    P. End of Trial
    P.End of Trial StatusOngoing
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