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    The EU Clinical Trials Register currently displays   43244   clinical trials with a EudraCT protocol, of which   7156   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2016-000647-14
    Sponsor's Protocol Code Number:15782601
    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:2016-03-30
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2016-000647-14
    A.3Full title of the trial
    Treatment with HMG-COA reductase inhibitor (simvastatin) of growth and bone abnormalities in children with Noonan syndrome : a phase III randomised, double-blind, placebo-controlled therapeutic trial
    Traitement par inhibiteur de l’HMG-CoA réductase (simvastatine) des anomalies de la croissance et de l’os des enfants présentant un syndrome de Noonan :
    un essai thérapeutique de phase III, multicentrique, randomisé, contrôlé contre placebo, en double aveugle.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment with simvastatin of growth and bone abnormalities in children with Noonan syndrome
    Traitement des anomalies osseuses et de croissance par la simvastatine chez les enfants atteints du syndrome de Noonan
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code number15782601
    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 SponsorUniversity Hospital Toulouse
    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 supportProgramme Hospitalier de Recherche Clinique, Enveloppe Nationale 2015
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Toulouse
    B.5.2Functional name of contact pointCaroline Peyrot
    B.5.3 Address:
    B.5.3.1Street AddressDirection de la Recherche Hôtel-Dieu, 2 rue Viguerie TSA 80035
    B.5.3.2Town/ cityToulouse
    B.5.3.3Post code31059
    B.5.4Telephone number+3305 61 77 84 86
    B.5.5Fax number+3305 61 77 84 11
    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. name Simvastatin
    D. of the Marketing Authorisation holderArrow Generique, 26 AVENUE TONY GARNIER 69007 LYON
    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 nameSimvastatin
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 placeboCapsule
    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
    Noonan syndrome
    Syndrome de Noonan
    E.1.1.1Medical condition in easily understood language
    Noonan syndrome
    Syndrome de Noonan
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluation of the effect of a 12 month simvastatin treatment on growth in Noonan syndrome children.
    Evaluation de l'effet d'un traitement de 12 mois par simvastatine sur la croissance chez les enfants atteints de syndrome de Noonan
    E.2.2Secondary objectives of the trial
    Evaluation of the effect of a 12-month simvastatin treatment on :
    - Other clinical (growth velocity, height, body mass index, waist circumference and hormonal (IGFBP-3) growth parameters
    - Growth plate and bone parameters
    - Cardiac function
    - Cognitive and behavioural deficits
    - Metabolism of lipids and carbohydrates
    - Study compliance
    - Adverse events
    Evaluer l’effet d’un traitement par simvastatine d’un an sur :
    - Les paramètres cliniques (vitesse de croissance, taille, indice de masse corporelle, tour de taille) et hormonaux (IGFBP-3)
    - Les paramètres osseux et de la plaque de croissance
    - La fonction cardiaque
    - Les déficits cognitifs et les troubles du comportement
    - Le métabolisme lipidique et glucidique
    - La compliance au traitement
    - Les effets secondaires
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Genetically confirmed Noonan syndrome (mutations in PTPN11, SOS1, RAF1, KRAS, RIT1, SPRED, or SHOC2 genes)
    - Female child between 6 to 15 years, without menses, and with bone age ≤ 13 years
    or male child between 6 to 16 years, and with bone age ≤ 14 years
    - Decreased growth velocity (≤ -1 SDS) and/or short stature (height ≤ - 2 SDS or ≤ -1.5 SDS under target height)
    - Informed consent obtained from child and parents
    - Participants with social security insurance or equivalent social protection.
    - Syndrome de Noonan confirmé génétiquement (mutation dans un des gènes suivants : PTPN11, SOS1, RAF1, KRAS, RIT1, SPRED, ou SHOC2)
    - Fille âgée de 6 à 15 ans, non réglée, dont l’âge osseux est ≤ 13 ans
    - Garçon âgé de 6 à 16 ans dont l’âge osseux est ≤ 14 ans
    - Diminution de la vitesse de croissance (≤ -1 DS) et/ ou retard de taille (taille ≤ - 2 DS ou ≤ -1.5 SDS de la cible génétique)
    - Consentement éclairé des titulaires de l’autorité parentale
    - Enfant affilié à un régime de sécurité sociale ou équivalent
    E.4Principal exclusion criteria
    - Weight < 20 kg
    - Contraindication to simvastatin treatment:
    o Progressive liver disease, increased serum levels of alanine aminotransferase (> 1.5 upper limit of normal [ULN]), aspartate aminotransferase (> 1.5 ULN), or creatine phosphokinase (> 1.5 ULN)
    o Known hypersensitivity to simvastatin
    o Treatment with CYP3A4 inhibitors (erythromycin, clarithromycin, ketoconazole, itraconazole cyclosporine, or danazol), gemfibrozil
    - Growth promoting therapies such as recombinant human GH or IGF-1 treatment during the last 3 months
    - Poids < 20 kg
    - Contre-indication au traitement par simvastatine :
    o Augmentation des taux sériques d’ASAT et/ou d’ALAT (> 1.5 fois la limite supérieure de la normale), ou de créatine phosphokinase (CPK) (> 1.5 fois la limite supérieure de la normale)
    o Hypersensibilité connue à la simvastatine
    Traitement par des inhibiteurs de la CYP3A4 (érythromycine, clarithromycine, kétoconazole, ou itraconazole, cyclosporine, danazol), gemfibrozil
    o Traitement stimulant de la croissance : GH et IGF-1 recombinantes humaines dans les trois mois précédant l’inclusion
    - Utilisation de promoteur de croissance tel que les hormones de croissance recombinante humaine ou un traitement par IGF-1
    E.5 End points
    E.5.1Primary end point(s)
    Change in serum levels of IGF-1 z-score during a 12-month treatment with simvastatin or placebo
    Variation des taux sériques d’IGF-1 (exprimés en z-score) au cours d’un traitement par simvastatine ou placebo
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline and month 1,3,6 and 12
    Baseline et aux mois 1,3,6 et 12
    E.5.2Secondary end point(s)
    Growth parameters :
    - Height, weight, body mass index and waist circumference
    - Serum IGFBP-3 levels

    Growth plates and bone parameters :
    - Serum C-type natriuretic peptide and amino-terminal propeptide of C-type natriuretic peptide (growth plate markers)
    - Serum levels of bone alkaline phosphatase (Bone formation parameters) and carboxy-terminal crosslinks (bone resorption parameters)
    - Bone mineral content, areal and volumetric bone mineral density of the whole body without the head and of the lumbar spine

    Cardiac function (echocardiography)
    - Left ventricular maximal wall thickness
    - Left ventricular diastolic function using mitral flow and pulsed Tissue Doppler to record the Ea, Aa, Ea/Aa and E/Ea ratios)

    Cognitive and behavioural deficits
    - Attention problems and internalising behavioural problems

    Metabolism of lipids and carbohydrates
    - Lipids levels (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides)
    - Serum levels of leptins and adipokines
    - Fat body mass measured by DXA
    - Insulin sensitivity indices based on fasting plasma insulin and glucose levels (HOMA and QUICKI)

    Study compliance
    - Analysis of questionnaires
    - Accounting for capsules

    Adverse events
    - Muscular symptoms (myalgia, myopathy, or rhabdomyolysis)
    - Increased CK levels
    - Increased levels of alanine aminotransferase and aspartate aminotransferase
    - Paramètres de croissance :
    o Taille, poids, indice de masse corporelle et tour de taille
    o Taux sériques d’IGFBP-3

    - Paramètres de la plaque de croissance et de l’os :
    o Taux sériques de C-type natriuretic peptide (CNP) et d’amino-terminal propeptide of CNP (NTproCNP) (marqueurs de la plaque de croissance)
    o Taux sériques des phosphatases alcalines osseuses (bone alkaline phosphatase, BAP), marqueur de formation osseuse, et des marqueurs de dégradation du collagène (carboxy-terminal collagen crosslinks, CTX), marqueur de résorption osseuse
    o Contenu minéral osseux, densité minérale osseuse de surface ou volumétrique du corps entier (sans tête) et du rachis lombaire (L2-L4), mesurés par DEXA

    - Fonction cardiaque (échographie cardiaque)
    o Epaisseur maximale de la paroi du ventricule gauche
    o Fonction diastolique du ventricule gauche en utilisant le flux mitral et le doppler tissulaire pulsé pour enregistrer les ratios Ea, Aa, Ea/Aa, and E/Ea

    - Déficits cognitifs et troubles du comportement
    o Echelle « Child Behavior Checklist » (CBCL)

    - Métabolisme lipidique et glucidique
    o Taux lipidiques (cholestérol total, cholestérol high-density lipoprotein, cholestérol low-density lipoprotein et triglycérides)
    o Taux sériques de leptine et adipokines
    o Masse grasse mesurée par DeXA
    o Indices de sensibilité à l’insuline basés sur les mesures de glycémie et insulinémie à jeun (HOMA et QUICKI)

    - Compliance au traitement
    o Analyse des questionnaires
    o Compte des capsules

    - Effets secondaires
    o Signes musculaires (myalgie, myopathie, ou rhabdomyolyse)
    o Augmentation des CPK
    o Augmentation des ASAT et ALAT
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Clinical examination parameters (height, weight, body mass index, waist circumference and blood pressure) : Baseline et months 1,3,6,9 et 12.

    - Cognitive and behavioural deficits : Baseline and month 12

    - Tolerance biological parameters (metabolism of lipids and carbohydrates, ALT, AST and CK) : Baseline and months 1,3,6,9 and 12

    - Efficacy biological parameters (IGFBP-3, bone alkaline phosphatase, CTX, glycemia, insulinemia, leptin) : Baseline and months 3,6 and 12

    - Bone age, body composition (DXA) and echocardiography : baseline and month 12

    - CNP and NTproCNP levels : baseline and months 1,3,6 and 12

    - Adverse events : 15 days after inclusion and months 1,3,6,9 and 12
    - Paramètres des examens cliniques (taille, poids, index de masse corporel, tour de taille et pression sanguine) : Baseline et mois 1,3,6,9 et 12.

    - Déficits du comportement et de la motivation : Baseline et mois 12

    - Paramètres biologiques de tolérance (métabolisme des lipides et des sucres, ALAT, ASAT et CK) : Baseline et mois 1,3,6,9 et 12

    - Paramètres biologique d'efficacité (IGFBP-3, phosphatase alcaline osseuse, CTX, glycémie, insulinémie, leptines) : Baseline et mois 3,6 et 12

    - Taux sériques de CNP et NT-proCNP : Mois 1

    - Age osseux, composition corporelle (DXA) et echocardiographie : Baseline et mois 12

    - Effets indésirables : 15 jours après inclusion et mois 1,3,6,9 et 12
    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 Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    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. 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 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 trial2
    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 concerned10
    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
    Dernière visite de suivi du dernier patient
    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 Yes
    F.1.1Number of subjects for this age range: 62
    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. of subjects for this age range: 31
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 31
    F.1.2Adults (18-64 years) No
    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 state62
    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)
    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 Decision2016-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-18
    P. End of Trial
    P.End of Trial StatusOngoing
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