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    Summary
    EudraCT Number:2019-003757-28
    Sponsor's Protocol Code Number:MEX-NM-301
    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:2020-11-20
    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 number2019-003757-28
    A.3Full title of the trial
    An Open-label, non-Comparative Study to Evaluate the Steady-State Pharmacokinetics, Safety, and Efficacy of Mexiletine in Adolescents and Children with Myotonic Disorders
    Étude ouverte non comparative visant à évaluer la pharmacocinétique, l’innocuité et l’efficacité de la mexilétine à l’état d'équilibre chez l’adolescent et l’enfant présentant des troubles myotoniques
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate Pharmacokinetics, Safety, and Efficacy of Mexiletine in Adolescents and Children with Myotonic Disorders
    Étude visant à évaluer la pharmacocinétique, l’innocuité et l’efficacité de la mexilétine chez l’adolescent et l’enfant présentant des troubles myotoniques
    A.4.1Sponsor's protocol code numberMEX-NM-301
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/155/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLupin Europe GmbH
    B.1.3.4CountryGermany
    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 supportLupin Atlantis Holdings SA
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLupin Healthcare (UK) Ltd.
    B.5.2Functional name of contact pointSenior Regulatory Affairs Manager
    B.5.3 Address:
    B.5.3.1Street AddressThe Urban Building, 2nd Floor, 3-9 Albert street
    B.5.3.2Town/ citySlough
    B.5.3.3Post codeSL1 2BE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441565751378
    B.5.5Fax number+441565751379
    B.5.6E-mailEU-RA@lupin.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 Namuscla
    D.2.1.1.2Name of the Marketing Authorisation holderLupin Europe GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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/3/14/1353 (EMA/OD/074/14)
    D.3 Description of the IMP
    D.3.1Product nameMexiletine 167 mg
    D.3.4Pharmaceutical form Capsule, hard
    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 INNMexiletine hydrochloride (HCl)
    D.3.9.1CAS number 5370-01-4
    D.3.9.3Other descriptive nameMEXILETINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB03281MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1353 (EMA/OD/074/14)
    D.3 Description of the IMP
    D.3.1Product nameMexiletine 83 mg
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Yes
    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 INNMexiletine hydrochloride (HCl)
    D.3.9.1CAS number 5370-01-4
    D.3.9.3Other descriptive nameMEXILETINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB03281MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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: 3
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1353 (EMA/OD/074/14)
    D.3 Description of the IMP
    D.3.1Product nameMexiletine 62 mg
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Yes
    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 INNMexiletine hydrochloride (HCl)
    D.3.9.1CAS number 5370-01-4
    D.3.9.3Other descriptive nameMEXILETINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB03281MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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
    Myotonic disorders: Nondystrophic myotonias (NDM) or myotonic dystrophies (DM, type 1 or type 2); ICD-10 code G71.1
    Myotonies non dystrophiques (NDM) ou dystrophies myotoniques (DM, type 1 ou 2)
    E.1.1.1Medical condition in easily understood language
    Myotonic disorders
    Troubles myotoniques
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10028658
    E.1.2Term Myotonic disorders
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The co-primary objectives of this study are: 1) to evaluate the safety of mexiletine in adolescents (aged 12 to <18 years) and children (aged 6 to <12 years) for the treatment of myotonic disorders; 2) to evaluate the efficacy of mexiletine for the treatment of myotonic disorders.
    1) Évaluer l’innocuité de la mexilétine chez l’adolescent (âgé de 12 à moins de 18 ans) et l’enfant (âgé de 6 à moins de 12 ans) pour le traitement de la myotonie ; 2) Évaluer l’efficacité de la mexilétine pour le traitement de la myotonie.
    E.2.2Secondary objectives of the trial
    The secondary objectives are: 1) to evaluate the efficacy of mexiletine for the treatment of myotonic disorders as assessed by patient-reported outcomes; 2) to evaluate effectiveness and tolerability of mexiletine as captured by Clinical Global Impression (CGI) scale indices; 3) to determine changes in health-related quality-of-life as measured by the PedsQL Quality of Life and Neuromuscular module; 4) to determine the steady-state pharmacokinetics (PK) of mexiletine in children (6 to <12 years) and adolescents (aged 12 to <18 years); 5) to assess the acceptability of the capsule formulation; and 6) to assess palatability of alternative administration (capsule content with milk/juice or sprinkled over yoghurt) by 5-point facial hedonic scale correlated with 100-point visual analogue scale (VAS).
    1) Évaluer l’efficacité de la mexilétine pour le traitement de la myotonie, telle qu’évaluée par les résultats rapportés par les patients ; 2) Évaluer l’efficacité et la tolérance de la mexilétine telles que mesurées par les indices sur l'échelle des impressions cliniques globales (CGI) ; 3) Déterminer les modifications de la qualité de vie liée à la santé telles que mesurées par le PedsQL Quality of Life and Neuromuscular module (module d'évaluation néuromusculaire et de la qualité de vie PedsQL) ; 4) Déterminer la pharmacocinétique de la mexilétine à l’état d'équilibre chez l’enfant (âgé de 6 à moins de 12 ans) et l’adolescent (âgé de 12 à moins de 18 ans) ; 5) Évaluer le degré acceptable de la formulation en gélule ; 6) Palatabilité d'une administration alternative (contenu d'une gélule avec du lait/jus ou saupoudré sur des aliments) selon l’échelle d’expression faciales en 5 points en corrélation avec une échelle visuelle analogique (EVA) sur 100 points.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients aged ≥ 6 and < 18 years who are able to comply with the study conditions;
    2. A genetically confirmed diagnosis of NDM or DM (DM1or DM2);
    3. Presence of clinical symptoms of myotonia (hand grip myotonia, myotonia in the leg muscles, any other myotonia symptoms);
    4. No significant cardiac abnormalities as determined by a cardiologist’s assessment of the ECG and echocardiogram performed within 3 months prior to enrolment in the study. (if not done within 3 months before trial, ECG and echocardiogram assessments will be performed at screening);
    5. No history of any significant liver disorder;
    6. Patients receiving mexiletine treatment agree to stop treatment at least 7 days prior to initiation of treatment with Namuscla;
    7. Patients receiving other antimyotonic treatment agree to stop treatment for at least 7 times the half-life of respective drug;
    8. Laboratory investigations for haematology, biochemistry, and urinalysis at screening are within normal range, or showing no clinically relevant abnormal values, as judged by the Investigator;
    9. Female patients of childbearing potential must be using an acceptable form of birth control as determined by the Investigator (e.g., oral contraception, implantable, injectable/transdermal hormonal contraception, intrauterine device (IUD), barrier methods), tubal ligation or have a vasectomized partner or are practicing abstinence;
    10. Patients able to provide assent to study participation and a parent or legal guardian able to sign written informed consent prior to study entry.
    1. Patients de sexe masculin ou féminin âgés de 6 à moins de 18 ans qui sont en mesure de respecter les exigences de l'étude ;
    2. Un diagnostic de MND, de DM1 ou de DM2 confirmé génétiquement ;
    3. Présence de symptômes cliniques de myotonie (myotonie de préhension, myotonie au niveau des muscles de la jambe et autres symptômes de myotonie) ;
    4. Aucune anomalie cardiaque significative telle que déterminée par évaluation de l’ECG et de l’échocardiogramme par un cardiologue réalisée dans un délai de 3 mois avant l’inclusion dans l’étude (Si non réalisées dans un délai de 3 mois avant l’essai, les évaluations de l’ECG et de l’électrocardiogramme seront menées lors de la sélection) ;
    5. Aucun antécédent de trouble hépatique significatif ;
    6. Les patients ayant reçu un traitement par la mexilétine acceptent d'arrêter le traitement au moins 7 jours avant l’instauration d'un traitement par Namuscla ;
    7. Les patients ayant reçu un autre traitement contre la myotonie acceptent d'arrêter le traitement pendant au moins 7 fois la demi-vie du médicament correspondant ;
    8. Les examens hématologiques, biochimiques et une analyse d'urine au dépistage indiquent des concentrations dans un intervalle normal ou une absence de valeurs anormales cliniquement significatives, d'après l'évaluation par l'investigateur ;
    9. Les patientes en âge de procréer doivent utiliser une forme de contraception acceptable telle que déterminée par l’investigateur (p. ex. contraception orale, dispositif implantable, injectable/transdermique, dispositif intra-utérin (DIU), méthode contraceptive de barrière), avoir fait l’objet d'une ligature des trompes ou pratiquer l'abstinence ;
    10. Patients en mesure de fournir leur accord pour une participation à l'étude, et parent ou tuteur légal devant signer le formulaire de consentement éclairé avant l’inclusion dans l'étude.
    E.4Principal exclusion criteria
    1. Any contra-indication to mexiletine as listed in the Namuscla Summary of Product Characteristics (SmPC):
    1.a. Hypersensitivity to the active substance, or to any of the excipients;
    1.b. Hypersensitivity to any local anaesthetic;
    1.c. Ventricular tachyarrhythmia;
    1.d. Complete heart block (i.e., third-degree atrioventricular block) or any heart block susceptible to evolve to complete heart block (first-degree atrioventricular block with markedly prolonged PR interval (≥ 200 ms) and/or wide QRS complex (≥ 120 ms), second-degree atrioventricular block, bundle branch block, bifascicular and trifascicular block);
    1.e. QT interval > 450ms;
    1.f. Myocardial infarction (acute or past), or abnormal Q-waves;
    1.g. Symptomatic coronary artery disease;
    1.h. Heart failure with ejection fraction <50%;
    1.i. Atrial tachyarrhythmia, fibrillation or flutter;
    1.j. Sinus node dysfunction (including sinus rate < 50 bpm);
    1.k. Co-administration with medicinal products inducing torsades de pointes;
    1.l. Co-administration with medicinal products with narrow therapeutic index;
    2. Any other neurological or psychiatric condition that might affect the assessment of the study measurements;
    3. Any clinically significant illness, laboratory findings, ECG, or other clinical symptoms, which in the opinion of the Investigator could affect the patient’s optimal participation in the study;
    4. Strong inducer or inhibitor of CYP2D6 or CYP1A2 within 7 days prior to study drug administration;
    5. Any concurrent illness, or medications which could affect the muscle function;
    6. Seizure disorder, diabetes mellitus requiring treatment by insulin;
    7. Pregnant or breastfeeding;
    8. Concurrent participation in any other clinical trial.
    1. Contre-indication à la mexilétine comme mentionnée dans le résumé des caractéristiques du produit (RCP) de Namuscla :
    1.a. Hypersensibilité au principe actif ou à l’un des excipients ;
    1.b. Hypersensibilité à un anesthésique local ;
    1.c. Tachyarythmie ventriculaire ;
    1.d. Bloc cardiaque complet (c.-à-d. bloc auriculo-ventriculaire du 3e degré) ou bloc cardiaque susceptible d'évoluer vers un bloc cardiaque complet (bloc auriculo-ventriculaire du premier degré avec intervalle PR sensiblement prolongé (≥ 200 ms) et/ou complexe QRS large (≥ 120 ms), bloc auriculo-ventriculaire du second degré, bloc de branche, bloc bifasciculaire et trifasciculaire) ;
    1.e. Intervalle QT > 450 ms ;
    1.f. Infarctus du myocarde (aigu ou antérieur) ou anomalies des ondes Q ;
    1.g. Coronaropathie symptomatique ;
    1.h. Insuffisance cardiaque à fraction d'éjection < 50 % ;
    1.i. Tachyarythmie, fibrillation ou flutter auriculaire ;
    1.j. Dysfonction du noeud sinusal (notamment une fréquence sinusale < 50 bpm) ;
    1.k. Co-administration avec des médicaments induisant des torsades de pointes ;
    1.l. Co-administration avec des médicaments présentant un indice thérapeutique étroit ;
    2. Autre maladie neurologique ou psychiatrique pouvant affecter les évaluations de l'étude ;
    3. Pathologie, résultats d’examen biologique, ECG ou autres symptômes cliniques cliniquement significatifs qui, selon le point de vue de l'investigateur, pourraient avoir un impact sur une participation optimale du patient à l'étude ;
    4. Inducteur ou inhibiteur puissant du CYP2D6 ou du CYP1A2 dans un délai de 7 jours précédant l'administration du médicament de l’étude ;
    5. Toute maladie concomitante, ou médicaments pouvant avoir un impact sur la fonction musculaire ;
    6. Trouble épileptique ou diabète sucré nécessitant une insulinothérapie ;
    7. Patientes enceintes ou qui allaitent ;
    8. Participation concomitante à un autre essai clinique.
    E.5 End points
    E.5.1Primary end point(s)
    1) Number and frequency of adverse events (AEs)/serious adverse events (SAEs);
    2) Incidence of Adverse events of special interest (AESI), i.e. neurological disorders (seizure, epilepsy, vertigo, headache, paraesthesia, dysgeusia, ataxia) or gastrointestinal disorders (abdominal pain, nausea, vomiting, diarrhoea, constipation, intestinal ucer, gastrointestinal bleeding, dysphagia, oesophageal ulceration);
    3) Changes in electrocardiogram (ECG) assessments from baseline;
    4) Efficacy of Namuscla treatment on the clinical outcomes (change from baseline to Days 14, 28, 42 and 56, respectively), based on the following functional evaluations: Mean change in VAS or Faces score for muscle stiffness (myotonia severity); Score of handgrip myotonia as quantitatively measured using a commercially available grip dynamometer and computerised capture system in standardised conditions.
    1) Nombre et fréquence des événements indésirables (EI) / événements indésirables graves (EIG), tout au long de l'étude pendant l’administration du traitement par Namuscla ;
    2) Incidence des événements indésirables d’intérêt particulier (EIIP) ;
    3) Modifications des évaluations ECG par rapport aux valeurs de référence, répétées lors de chaque visite de l'étude ;
    4) Efficacité du traitement par Namuscla sur les résultats cliniques (modification depuis l’inclusion jusqu’aux jours 14, 28, 42 et 56 respectivement) selon les évaluations fonctionnelles suivantes : variation moyenne du score sur l'échelle visuelle analogique (EVA) ou du score d’expressions faciales pour la raideur musculaire (sévérité de la myotonie) et score de la myotonie de préhension selon la mesure quantitative à l’aide d'un dynamomètre de force de préhension disponible dans le commerce et d'un système de recueil informatisé dans des conditions normalisées.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) Throughout the study while on treatment with mexiletine;
    2) Throughout the study while on treatment with mexiletine;
    3) Screening visit, baseline visit (Day 0), 1st titration visit (Day 14), 2nd titration visit (Day 28), PK visit (Day 42) and at the end of the study (Day 56);
    4) Baseline visit (Day 0), 1st titration visit (Day 14), 2nd titration visit (Day 28), PK visit (Day 42) and at the end of the study (Day 56).
    1) Tout au long de l'étude ;
    2) Tout au long de l'étude ;
    3) A la visite d'inclusion V0, à la visite V1 (J0), à la visite V2 (J14), à la visite V3 (J28), à la visite V4 (J42) et à la visite V5 (J56 = fin de l'étude);
    4) A la visite V1 (J0), à la visite V2 (J14), à la visite V3 (J28), à la visite V4 (J42) et à la visite V5 (J56 = fin de l'étude).
    E.5.2Secondary end point(s)
    1) Mean change in VAS or Faces score for muscle pain, weakness and fatigue from baseline to Days 14, 28, 42 and 56, respectively;
    2) Clinical myotonia assessment from baseline to Days 14, 28, 42 and 56, respectively: mean change in time to open the eyes after forced eye closure as measured on a stopwatch (when eyelid myotonia present); clinical improvement in flexor myotonia (right hand flexor muscles); and mean change in time to perform Timed-up and go (TUG) test;
    3) Mean change from baseline to Day 56 in Paediatric Quality of Life (PedsQL) score;
    4) Clinical Global Impression (CGI) scores (efficacy and tolerability) evaluated by the patient, a parent or proxy and by the investigator;
    5) Mean change from baseline to Day 56 in Myotonia Behaviour Scale (MBS) scores;
    6) Changes in clinical laboratory values (i.e.biochemistry, haematology, and urinalysis etc.) from baseline to Day 56;
    7) Acceptability of the capsule formulation with respect to the swallowability. It will be assessed by interviewing patients and their caregivers at Day 56;
    8) Palatability of alternative administration (capsule content with milk/juice or sprinkled on food) by 5-point facial hedonic scale correlated with 100-point VAS at each clinic visit;
    9) Steady-state PK parameters: Cmax-ss (peak concentrations during the dosing interval at steady-state); Ctrough-ss (observed concentration at the end of a dosing interval, immediately before next administration); AUC0-tau (area under the concentration time curve for one dosing interval at steady-state); Cav-SS (average plasma concentration at steady-state); Tmax-SS (time until Cmax-SS is reached); Fluctuation (defined as 100*( Cmax-SS - Cmin-SS)/ Cav-SS).
    1) Variation moyenne du score sur l’EVA ou du score d’expressions faciales pour la douleur, la faiblesse et la fatigue musculaires depuis l’inclusion jusqu'aux jours 14, 28, 42 et 56 respectivement ;
    2) Évaluation d'une myotonie clinique depuis l’inclusion jusqu’aux jours 14, 28, 42 et 56 respectivement : variation du délai d’ouverture de l’oeil après fermeture forcée, tel que mesuré à l’aide d'un chronomètre (en cas de présence d’une myotonie palpébrale), amélioration clinique de la myotonie des muscles fléchisseurs (muscles fléchisseurs de la main droite), variation moyenne du temps mis pour réaliser le test chronométré du lever de chaise de Mathias (TUG) ;
    3) Variation moyenne de la qualité de vie liée à la santé telle que mesurée par le score au module PedsQL entre l’inclusion et le jour 56 ;
    4) Scores sur l'échelle des impressions cliniques globales (CGI) (efficacité et tolérance) évalué par le patient, un parent ou une personne ayant procuration et par l’investigateur à l’inclusion et au jour 56 ;
    5) Variation moyenne des scores sur l’échelle du comportement dans la myotonie (MBS) entre l’inclusion et le jour 56 ;
    6) Variations des valeurs biologiques cliniques entre l’inclusion et le jour 56 ;
    7) Acceptabilité de la formulation en gélule par rapport à la capacité à avaler. Une évaluation sera réalisée par les patients interrogés et leurs aidants au jour 56 ;
    8) Palatabilité d'une administration alternative (contenu d'une gélule avec du lait/jus ou saupoudré sur des aliments) selon l’échelle d’expression faciales en 5 points en corrélation avec une échelle visuelle analogique (EVA) sur 100 points lors de chaque visite à la clinique ;
    9) Paramètres pharmacocinétiques à l’état d’équilibre : Concentration maximale (Cmax), Concentration résiduelle (Crés), Aire sous la courbe pour l’intervalle posologique (AUCtau), Concentration moyenne (Cmoy), Durée maximale (Tmax), Fluctuation.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Baseline visit (Day 0), 1st titration visit (Day 14), 2nd titration visit (Day 28), PK visit (Day 42) and at the end of the study (Day 56);
    2) Baseline visit (Day 0), 1st titration visit (Day 14), 2nd titration visit (Day 28), PK visit (Day 42) and at the end of the study (Day 56);
    3) Baseline visit (Day 0), 1st titration visit (Day 14), 2nd titration visit (Day 28), PK visit (Day 42) and at the end of the study (Day 56);
    4) At the end of the study (Day 56);
    5) Baseline visit (Day 0) and at the end of the study (Day 56);
    6) Screening visit and at the end of the study (Day 56);
    7) At the end of the study (Day 56);
    8) Baseline visit (Day 0), 1st titration visit (Day 14), 2nd titration visit (Day 28), PK visit (Day 42) and at the end of the study (Day 56);
    9) PK visit (Day 42).
    1) A la visite V1 (J0), à la visite V2 (J14), à la visite V3 (J28), à la visite V4 (J42) et à la visite V5 (J56 = fin de l'étude) ;
    2) A la visite V1 (J0), à la visite V2 (J14), à la visite V3 (J28), à la visite V4 (J42) et à la visite V5 (J56 = fin de l'étude) ;
    3) A la visite V1 (J0), à la visite V2 (J14), à la visite V3 (J28), à la visite V4 (J42) et à la visite V5 (J56 = fin de l'étude) ;
    4) A V5 ;
    5) A V1 et à V5 ;
    6) A V0 et à V5 ;
    7) A V5 ;
    8) A la visite V1 (J0), à la visite V2 (J14), à la visite V3 (J28), à la visite V4 (J42) et à la visite V5 (J56 = fin de l'étude) ;
    9) A V4.
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Paediatric investigation plan
    Plan d'investigation pédiatrique
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned2
    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 (Day 56), or earlier in case of early discontinuation. Criteria for treatment discontinuation are: 1) An adverse event, which in the opinion of the Investigator and/or Sponsor, necessitates discontinuation of treatment; and/or 2) The patient becomes pregnant during the study period.
    Dernière visite de la dernière personne participant à l’essai.
    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 months6
    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: 14
    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: 7
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 7
    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 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 No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Paediatric population
    Population pédiatrique
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state14
    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)
    End-of-treatment visit will occur at Day 56 (or earlier in case of early discontinuations). A seventh visit, a safety follow-up visit, will take place 7 days after the last study dose only in patients who do not roll-over into Paediatric Investigation Plan (PIP) Study 7. Patients enrolling in PIP Study 7 (MEX-NM-303) will sign the informed consent at or prior to the last visit.
    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 Decision2020-02-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-24
    P. End of Trial
    P.End of Trial StatusOngoing
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