Clinical Trials Register

Summary
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

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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2020-000250-94

A.3

Full title of the trial

Mutation-specific therapy for the long QT syndrome

Terapia mutazione-specifica per la sindrome del QT lungo

A.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

MAST2

A.4.1

Sponsor's protocol code number

MAST2

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	ISTITUTO AUXOLOGICO ITALIANO
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AIFA - Italian Medicines Agency
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Istituto Auxologico Italiano
B.5.2	Functional name of contact point	Direzione Area Ricerca Scientifica
B.5.3	Address:
B.5.3.1	Street Address	Via L. Ariosto 45
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20145
B.5.3.4	Country	Italy
B.5.6	E-mail	trials@auxologico.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ORKAMBI - 200 MG / 125 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE - BLISTER (ACLAR/PVC/ALLUMINIO) - 112 (4X28) COMPRESSE (CONFEZIONE MULTIPLA)
D.2.1.1.2	Name of the Marketing Authorisation holder	VERTEX PHARMACEUTICALS (IRELAND) LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Orkambi
D.3.2	Product code	[Orkambi]
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	Lumacaftor
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	Ivacaftor
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	125
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Long QT syndrome

Sindrome del QT lungo

E.1.1.1

Medical 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.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10057926
E.1.2	Term	Long QT syndrome congenital
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary objectives of the trial

No secondary objectives

Non ci sono obiettivi secondari

E.2.3

Trial contains a sub-study

E.3

Principal 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.4

Principal 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.5.1

Primary end point(s)

Change in QTc interval after drug treatment

Variazione dell’intervallo QTc dopo somministrazione del farmaco.

E.5.1.1

Timepoint(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.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women 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.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-07-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-21

P. End of Trial
P.	End of Trial Status	Ongoing

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