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    EudraCT Number:2020-000250-94
    Sponsor's Protocol Code Number:MAST2
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-17
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-000250-94
    A.3Full title of the trial
    Mutation-specific therapy for the long QT syndrome
    Terapia mutazione-specifica per la sindrome del QT lungo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Novel therapy for the Long QT Syndrome based on the mechanism of action of the disease-causing mutations
    Nuova terapia per la sindrome del QT lungo basata sul meccanismo di azione delle mutazioni causanti la malattia
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberMAST2
    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.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 supportAIFA - Italian Medicines Agency
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIstituto Auxologico Italiano
    B.5.2Functional name of contact pointDirezione Area Ricerca Scientifica
    B.5.3 Address:
    B.5.3.1Street AddressVia L. Ariosto 45
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20145
    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. of the Marketing Authorisation holderVERTEX PHARMACEUTICALS (IRELAND) LIMITED
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameOrkambi
    D.3.2Product code [Orkambi]
    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.3.9.2Current sponsor codeLumacaftor
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeIvacaftor
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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 Information not present in EudraCT
    D. therapy medical product Information not present in EudraCT
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Long QT syndrome
    Sindrome del QT lungo
    E.1.1.1Medical condition in easily understood language
    Genetic disease associated with increased risk of sudden cardiac death
    Malattia genetica che mette a rischio di morte cardiaca improvvisa
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10057926
    E.1.2Term Long QT syndrome congenital
    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
    To evaluate the efficacy of Orkambi in reducing the QT corrected for HR in patients with a KCNH2 mutation causing a trafficking effect.
    Determinare l’efficacia di Orkambi nell’accorciare l’intervallo QT corretto per la frequenza cardiaca (QTc) sull’ECG di superficie nei pazienti LQT2 con mutazioni di Classe II che, per l’appunto, alterano il trafficking.
    E.2.2Secondary objectives of the trial
    No secondary objectives
    Non ci sono obiettivi secondari
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Informed consent: it is requested that the partipants understand the nature of the study and can give their voluntary conset after being fully informed, after having received satisfying replies to their questions regarding the study, and all the authorizations according to local requirements. The informed consent form will previously be approved by the local Ethics Committee e will have to be dated and signed before enrollment in the study, in accordance with the rules of Good Clinica Practice (ICH-GCP) and the local requirements.

    • Age and gender: participants of both the male and female sex aged between 18 and 65 years will be included

    • Mutations: the study will enrol patients with LQT2, i.e., with pathogenic mutations on the KCNH2 gene, that present such functional characterization that classifies them as class II mutations, namely mutations that cause a trafficking defect. This characterization includes, but is not limited to, patch clamp data in single cells, immunofluorescence data, positive reactions to drugs that correct the trafficking defect in vitro. Some examples of trafficking-deficient variants in our pateint database are: KCNH2-p.Y43C, KCNH2-p.A78P, KCNH2-p.R534C, KCNH2-p.A561V, KCNH2-p.W568C, KCNH2-p.G572S, KCNH2-p.P596L, KCNH2-p.G601S, KCNH2-p.G604S, KCNH2-p.V612A, KCNH2-p.T613M, KCNH2-p.A614V, KCNH2-p.N629S, KCNH2-p.N633S, KCNH2-p.T634I, KCNH2-p.S641F, KCNH2-p.V644F, KCNH2-p.R752W, KCNH2-p.F805S, KCNH2-p.S818L, KCNH2-p.R823W, KCNH2-p.N861H, KCNH2-p.R863*, KCNH2-p.W927*, KCNH2-p.W1001*, KCNH2-p.R1014*. Other variants that belong to the same class of mutations will inevitably be detected in the next years.

    • Consent of the patient to not participate in any other clinical study during the entire period of participation in the present study

    • Women with child-bearing potential (pre-menopausal women, less than two years after start of menopause and women who are not surgically sterile) must use a highly effective contraceptive method from 30 days before enrollment in the study until 28 days after the last administration of study drug. It is specified that the sole use of hormonal contraception, both oral, injectable, transdermic and implantable cannot be considered an effective contraceptive method. Orkambi (Lumacaftor/ivacaftor) may reduce the exposure to the hormonal contraceptives and possibly cause their ineffectiveness. Male patients with a female partner with child-bearing potential must use 2 forms of contraception (one of which should be a double-barrier method) from enrolment in the study until 28 days after the last administration of study drug. Highly effective contraceptive methods are: i) abstinence, ii) surgical sterilization (=6 months post-surgery), iii) intrauterine device or intrauterine system, iv) oral contraceptives combined with a barrier method, v) double-barrier method (e.g., male condom or diaphragm with vaginal spermicides).
    • Consenso informato: i partecipanti dovranno poter comprendere la natura dello studio e poter rilasciare un consenso volontario e pienamente informato, dopo aver ottenuto risposte soddisfacenti a tutti i loro quesiti sullo studio, e tutte le autorizzazioni richieste dalla normativa locale vigente. Il consenso informato sarà preventivamente approvato dal Comitato Etico istuzionale e dovrà essere datato e firmato prima dell’ammmissione allo studio clinico, in accordo alla Buona pratica clinica (ICH-GCP) e alle normative vigenti

    • Età e sesso: verranno inclusi partecipanti sia di sesso maschile che femminile di età compresa tra i 18 e i 65 anni

    • Mutazioni: verranno arruolati pazienti LQT2, ossia con mutazioni patogenetiche sul gene KCNH2, che presentino una caratterizzazione funzionale che consenta loro di essere classificate come mutazioni di classe II, ossia mutazioni che causino un difetto di trafficking. Questa caratterizzazione comprende, ma non è limitata a, dati di patch clamp in singola cellula, studi di immunofluorescenza, risposta positiva a farmaci per la correzione del difetto di trafficking in vitro. Alcuni esempi di varianti di trafficking già presenti nel nostro database di pazienti sono: KCNH2-p.Y43C, KCNH2-p.A78P, KCNH2-p.R534C, KCNH2-p.A561V, KCNH2-p.W568C, KCNH2-p.G572S, KCNH2-p.P596L, KCNH2-p.G601S, KCNH2-p.G604S, KCNH2-p.V612A, KCNH2-p.T613M, KCNH2-p.A614V, KCNH2-p.N629S, KCNH2-p.N633S, KCNH2-p.T634I, KCNH2-p.S641F, KCNH2-p.V644F, KCNH2-p.R752W, KCNH2-p.F805S, KCNH2-p.S818L, KCNH2-p.R823W, KCNH2-p.N861H, KCNH2-p.R863*, KCNH2-p.W927*, KCNH2-p.W1001*, KCNH2-p.R1014*. Altre varianti sempre appartenenti alla stessa classe di mutazioni si aggiungeranno inevitabilmente nei prossimi anni.

    • Consenso del paziente al non arruolamento in nessun altro studio clinico per la durata della sua partecipazione allo studio.

    • Nel caso di donne in età fertile (donne che non hanno raggiunto la menopausa, donne in stato post-menopausale da meno di 2 anni e donne che non siano chirurgicamente sterili), le pazienti devono utilizzare un metodo di contraccezione altamente efficace a partire da 30 giorni prima dell’ingresso dello studio fino a 28 giorni dopo l’ultima dose del farmaco in studio. Si precisa che che per le donne potenzialmente fertili non si deve fare affidamento sui contraccettivi ormonali, inclusi quelli orali, iniettabili, transdermici e impiantabili, come metodo di contraccezione efficace. Orkambi (Lumacaftor/ivacaftor) infatti può ridurre l’esposizione ai contraccettivi ormonali con possibile inefficacia. I pazienti di sesso maschile con un partner femminile in età fertile devono concordare 2 forme di contraccezione (uno dei quali deve essere un metodo a doppia barriera) dall’ingresso allo studio fino a 28 giorni dopo l’ultima dose del farmaco in studio. I metodi contraccettivi altamente efficaci includono: i) astinenza, ii) sterilizzazione chirurgica (=6 mesi postchirurgia), iii) dispositivo intrauterino o sistema intrauterino, iv) contraccettivo orale più un metodo di barriera, v) metodo a doppia barriera (ad es. Preservativo maschile o diaframma con crema spermicida vaginale).
    E.4Principal exclusion criteria
    • Absence of one or more of the preceeding inclusion criteria

    • Hypersensitivity to the active substance (to one or both active substances) or to one of the excipients.

    • Pregnancy (established before enrollment by positive urine pregnancy test in potentially fertile women) or breastfeeding

    • Participation in a clinical study in whch an experimental drugs has been administered less than 30 days or less than 5 half-lives before the present study drug

    • Any clinical condition that in the opinion of the investigator causes the patients not to be suitable for the study and/or that may involve an unreasonable/significant risk for the participants, thereby changing the interpretation of that data and affecting the continuation of the study

    • Other important cardiac diseases and in particular: cardiomyopathies and myocarditis, pericardial diseases, other associated channelopathies, ischemic heart disease, heart failure, pulmonary heart disease, severe valuvulopathies, rhythm alterations such as atrial fibrillation or atrial flutter, complete right or left bundle branch block, advanced atrio-ventricular blocks, uncontrolled arterial hypertension on beta-blocker therapy

    • Significant extracardiac diseases and in particular:
    o renal failure. In accordance with the SmPC, patients with severe (estimated GFR <30 mL/min/1.73 m2) and moderate (estimated GFR 30-60 mL/min/1.73 m2) renal impairment at screening are excluded
    o impairment of liver function. In accordance with the SmPC, patients with severe (Child-Pugh Class C) and moderate (Child-Pugh Classe B) liver function impairment are excluded
    o important diseases of the respiratory system and in particular: any pulmonitis, obstructive bronchopulmonary disease with FEV1 <80%, asthmatic bronchitis, infiltrative lung disease, lung emboly, pulmonary hypertension, idiopathic pulmonary fibrosis, pneumothorax, neoplasms of lungs and pleura
    o important neurological diseases and in particular: epilepsy, cerebral hemorrhage, stroke, multiple sclerosis, cerebral tumours, cerebral or spinal traumas, Parkinson’s disease, cognitive deterioration and Alzheimer’s disease

    • Chronic use of therapies other than beta-blocker treatment and intake of any potassium/magnesium supplement that the patient may use chronically or intermittently (oral contraceptives are allowed, but must be interrupted during the study).
    • Assenza di uno o più dei precedenti criteri di inclusione

    • Ipersensibilità al principio attivo (ad uno o entrambi i principi attivi) o ad uno qualsiasi degli eccipienti

    • Pazienti gravide (condizione accertata prima dell’arruolamento tramite test di gravidanza su urine positivo per donne potenzialmente fertili) o in allattamento

    • Partecipazione ad uno studio clinico in cui è stato somministrato un farmaco sperimentale entro 30 giorni o 5 emivite prima del farmaco in studio

    • Qualsiasi condizione clinica che a giudizio dello sperimentatore renderebbe il paziente non idoneo per lo studio e/o che presenti un rischio irragionevole/significativo per i partecipanti, alterando l’interpretazione dei dati e la continuazione dello studio

    • Altre patologie cardiache rilevanti e nello specifico: cardiomiopatie e miocarditi, malattie del pericardio, altre canalopatie associate, cardiopatia ischemica, scompenso cardiaco, cuore polmonare, valvulopatie severe, alterazioni del ritmo come fibrillazione atriale o flutter atriale, blocchi completi di branca destra o sinistra, blocchi atrio-ventricolari avanzati, ipertensione arteriosa non controllata con la sola terapia beta-bloccante.

    • Significative patologie extracardiache e nello specifico:
    o insufficienza renale. In accordo con l’RCP si escludono i pazienti con compromissione renale grave (GFR stimata <30 mL/min/1,73 m2) e moderata (GFR stimata tra 30 e 60 mL/min/1,73 m2) al momento dello screening
    o compromissione epatica. In accordo con l’RCP si escludono pazienti con compromissione epatica grave (Child-Pugh Classe C) e con compromissione epatica moderata (Child-Pugh Classe B)
    o malattie dell’apparato respiratorio rilevanti e nello specifico: polmoniti di qualunque natura, broncopneumopatia cronica ostruttiva con VEMS <80% del predetto, asma bronchiale, pneumopatie infiltrative, embolia polmonare, ipertensione polmonare, fibrosi polmonare idiopatica, pneumotorace, patologie tumorali del polmone e della pleura.
    o patologie neurologiche rilevanti e nello specifico: epilessia, emorragia cerebrale, ictus, sclerosi multipla, tumori cerebrali, i traumi cerebrali o del midollo spinale, morbo di Parkinson, decadimento cognitivo e sindrome di Alzheimer

    • Assunzione in cronico di altre terapie ad esclusione della terapia beta-bloccante e di eventuali integratori di potassio/magnesio che il paziente potrebbe fare in cronico o a cicli (i contraccettivi orali sono consentiti, ma devono essere interrotti durante la fase di sperimentazione).
    E.5 End points
    E.5.1Primary end point(s)
    Change in QTc interval after drug treatment
    Variazione dell’intervallo QTc dopo somministrazione del farmaco.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From 3 up to 7 days of oral therapy
    Dai 3 ai 7 giorni della terapia
    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 Yes
    E.6.5Efficacy Yes
    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) Yes
    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 No
    E.8.1.3Single blind No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    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 Information not present in EudraCT
    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
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial 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: 20
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2021-06-17. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 20
    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 perform their regular follow-up visits
    I pazienti continueranno con i loro follow-up regolari, come da prassi clinica
    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 Decision2020-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-21
    P. End of Trial
    P.End of Trial StatusOngoing
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