Clinical Trials Register

Summary
EudraCT Number:	2014-002627-10
Sponsor's Protocol Code Number:	RILUMEX
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:	2020-11-05
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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-002627-10

A.3

Full title of the trial

A randomized, double-blind, controlled, monocenter, pivotal phase IIb study to evaluate the efficacy and safety of riluzole versus mexiletine in patients with non dystrophic myotonia mutated in SCN4A or CLCN1 genes.

Studio pilota fase IIb, randomizzato, in doppio cieco, controllato, monocentrico, per valutare l'efficacia e la sicurezza di riluzolo vs mexiletina in soggetti con miotonia non distrofica mutati nei geni SCN4A o
CLCN1.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Pivotal study to evaluate the efficacy and safety of riluzole versus mexiletine in patients with non dystrophic myotonia mutated in SCN4A or
CLCN1 genes.

Studio clinico pilota per valutare l'efficacia e la sicurezza di riluzolo rispetto mexiletina in pazienti affetti da miotonia non distrofica mutati nei geni
SCN4A o CLCN1.

A.3.2

Name or abbreviated title of the trial where available

RILUMEX

A.4.1

Sponsor's protocol code number

RILUMEX

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	FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
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	MINISTERO DELLA SALUTE - FONDI 5 X 1000
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	Fondazione IRCCS Istituto Neurologico Carlo Besta
B.5.2	Functional name of contact point	Servizio Ricerca e Sviluppo Clinico
B.5.3	Address:
B.5.3.1	Street Address	via Celoria 11
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	0223942321
B.5.5	Fax number	0223943569
B.5.6	E-mail	crc@istituto-besta.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	RILUZOLO TEVA - 50 MG COMPRESSE RIVESTITE CON FILM 90 COMPRESSE IN BLISTER AL/PVC
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
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	RILUZOLO
D.3.4	Pharmaceutical form	Capsule, hard
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.3.8	INN - Proposed INN	RILUZOLO
D.3.9.2	Current sponsor code	N07XX02
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	50
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/13/1189
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Capsule, hard
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.3.8	INN - Proposed INN	MEXILETINA CLORIDRATO
D.3.9.2	Current sponsor code	700002138
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	50
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

NDM patients with mutations in SCN4A or CLCN1 gene

Miotonie non distrofiche con mutazione nei geni SCN4A o CLCN1

E.1.1.1

Medical condition in easily understood language

Patients with myotonic phenomenon

Pazienti con fenomeno miotonico

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10029205
E.1.2	Term	Nervous system disorders
E.1.2	System Organ Class	10029205 - Nervous system 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 assess the efficacy of riluzole compared to mexiletine in reducing severity of myotonia in patients affected by NDM with mutations in CLCN1 or SCN4A genes through stiffness evaluation by the Interactive Web Response diary

Valutare l'efficacia di riluzolo comparato a mexiletina nei pazienti affetti da MND mutati nei geni SCN4A o CLCN1attraverso stima della rigidit¿ mediante Interactive Web Response Diary

E.2.2

Secondary objectives of the trial

- To assess the safety and tolerability of riluzole in patients affected by NDM with mutations in CLCN1 or SCN4A gene
- To assess the efficacy of riluzole compared to mexiletine in reducing severity of myotonia in patients affected by NDM with mutations in
CLCN1 or SCN4A genes, assessed by other measures of functionality and also its impact on quality of life.

- valutare la sicurezza e la tollerabilit¿ di riluzolo nei pazienti affetti da MND mutati nei geni SCN4A o CLCN1
- testare l'efficacia di riluzolo comparato a mexiletina nel ridurre il grado di severit¿ della miotonia nei pazienti affetti da MND mutati nei geni SCN4A o CLCN1attraverso misure di funzionalit¿ ed il relativo
impatto sulla qualit¿ di vita

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Aged at least 18 years.
- Clinical signs or symptoms of myotonia.
- Myotonic potentials on electromyography.
- Genetically confirmed NDM (patients mutated in SCN4A or CLCN1
gene).
- Written informed consent.
- Daily access to a personal computer and internet connection, for IWR
diary report.

a) età superiore a 18 aa.
b) Fenomeno miotonico clinicamente evidente.
c) Evidenza di miotonia all'esame elettromiografico ad ago.
d) Mutazione nei geni SCN4A o CLCN1.
e) Consenso informato scritto.
f) Disponibilità quotidiana per compilazione interactive web response (IWR) diary.

E.4

Principal exclusion criteria

- Other neurological conditions that might affect the study assessments.
- Genetic confirmation of DM1 (more than 50 repeats of CTG) or DM2.
- Existing atrial flutter or fibrillation or other cardiac conduction defects, as evidenced on ECG at screening visit, including but not limited to the following conditions: malignant arrhythmia or cardiac conduction disturbances (e.g., second degree AV block, third degree AV block, or prolonged QT interval). Any cardiological controindications to mexiletine use will be excluded by a cardiologist. If required by the cardiologist, the patient will undergo heart echo scan and/or Holter ECG.
- Existing permanent pacemaker.
- Current use of any of the following antiarrhythmic medications for a cardiac disorder: flecainide acetate, encainide, disopyramide, procainamide, quinidine, propafenone, or mexiletine.
- Currently use of mexiletine for myotonia in 7 days before randomization.
- Use of medications for myotonia, such as phenytoin and flecainide acetate, within 5 days of study entry, carbamazepine within 3 days of study entry; or propafenone, procainamide, disopyramide, quinidine, and encainide within 2 days of study entry.
- Use of medications that produce myotonia, which may include fibrate acid derivatives, hydroxymethylglutaryl CoA reductase inhibitors, chloroquine, and colchicines.
- Kidney or liver disease or abnormally high levels of liver enzymes such as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), alkaline phosphatase (AP), GGT, serum bilirubin, except for Gilbert’s Disease:
The investigator should be guided by the following criteria:
¿ Any single transaminase may not exceed 3x times upper limits of normal (ULN). A single parameter elevated up to and including 3 x ULN should be re-checked as soon as possible, and in all cases, at least prior to randomization, to rule out any lab error. Normal lab values are shown in table 3.
¿ AP and/or GGT may not exceed 2x times ULN. A single parameter elevated up to and including 2 x ULN should be re-checked as soon as possible, and in all cases, at least prior to randomization, to rule out any lab error.
¿ If the total bilirubin (TBL) concentration is increased above 1.5x ULN, total bilirubin should be differentiated into the direct and indirect reacting bilirubin. In any case, serum bilirubin should not exceed the value of 1.6 mg/dL.
- Known heart failure or symptomatic cardiomyopathy or recent cardiac infarction (<3 months before randomization).
- Significant coagulopathy, platelet count less than 75,000/mm3, hemoglobin less than 11.0 g/dL.
- Seizure disorder.
- Currently pregnant or breastfeeding.

a) Altre patologie neurologiche che possano influenzare la valutazione dei diversi endpoint.
b) conferma genetica di DM1 (maggiore 50 ripetizioni di CTG) o DM2
c) Flatter o fibrillazione atriale o altri difetti di conduzione cardiaca, come documentato all'ECG alla visita di screening, incluse ma non limitate alle seguenti condizioni: aritmia magligna o disturbi di conduzione cardiaca (per es. blocco atrioventricolare di secondo o terzo grado o aumentato intervallo QT). Ogni controindicazione cardiologica all'uso di mexiletina sarà escluso da un cardiologo. Se richiesto dal cardiologo il paziente sarà sottoposto a ecografia cardiaca e/o Holter ECG.
d) Pacemaker permanente.
e) Terapia concomitante con uno dei seguenti antiartimici per patologia cardiaca: flecainide acetate, encainide, disopiramide, procainamide, chinidina, propafenone o mexiletina.
f) Assunzione di mexiletina nei sette giorni precedenti la randomizzazione.
g) Assunzione di farmaci per il trattamento della miotonia, come fenitoina e flecainide acetate, entro 5 giorni dall'ingresso nello studio, carbamazepina entro 3 giorni dall'ingresso nello studio o propafenone, procainamide, disopiramide, chinidina ed encainide entro 2 giorni dall'ingresso nello studio.
h) Assunzione terapie che determinano miotonia che può includere fibrati, inibitori della idrossimetilglutaril coenzima Areduttasi, clorochina e colcichine.
i) Patologia epatica o renale, aumento enzimi epatici come aspartato aminotransferasi (AST) e/o alanina aminotransferasi (ALT), fosfatasi alcalina (AP), GGT, bilirubina sierica, eccetto per malattie di Gilbert.
Lo sperimentatore dovrebbe essere guidato dai seguenti criteri:
-ogni singola transaminasi non dovrebbe superare 3 volte il limite superiore di normalità (LSN). Un singolo parametro elevato fino a o uguale a 3 volte il LSN, dovrebbe essere ricontrollato il prima possibile, e in tutti i casi almeno prima della randomizzazione, per escludere qualunque errore di laboratorio. I normali valori di laboratorio sono mostrati nella tabella 3 allegata al protocollo.
- AP e/o GGT non dovrebbero superare di 2 volte il LSN. Un singolo parametro elevato fino a o uguale a 2 volte il LSN, dovrebbe essere ricontrollato il prima possibile, e in tutti i casi almeno prima della randomizzazione, per escludere qualunque errore di laboratorio.
- se la concentrazione della bilirubina totale (TBL) è aumentata sopra 1,5 LSN la TBL dovrebbe essere differenziata nella bilirubina diretta e indiretta. In ogni caso la bilirubina sierica non dovrebbe superare il valore di 1,6 mg/dL.
m) Insufficienza cardiaca nota o cardiomiopatia. sintomatica o recente infarto miocardico (inferiore di 3 mesi prima della randomizzazione).
n) Significativa coagulo patia, conta piastrinica inferiore <75.000/mm3, emoglobina inferiore a 11,0 g/dL
o) Crisi comiziali.
p) Gravidanza od allattamento in atto.

E.5 End points

E.5.1

Primary end point(s)

Patient-reported stiffness on the Interactive Web Response (IWR) diary, a variant of interactive voice response (IVR) diary. IVR system assessed symptom severity and frequency in four categories: muscle stiffness,weakness, pain, and tiredness (Statland et al., 2011).

Valutazione rigidità secondo IWR diary (versione in italiano), a scadenza giornaliera, da eseguire nelle settimane 1, 5, 9 e 13.

E.5.1.1

Timepoint(s) of evaluation of this end point

1, 5, 9, 13 weeks

1, 5, 9, 13 settimane

E.5.2

Secondary end point(s)

a) Patient-reported Pain, Weakness and Tiredness on the IWR diary. b) Quantitative measure of handgrip myotonia (seconds). c) Clinical hand-grip myotonia evaluation (seconds). d) Individualized Neuromuscular Quality of Life Scale (INQoL). e) Short Form 12 (SF-12)

a) valutazione dolore, debolezza e stanchezza secondo IWR diary (versione in italiano), a scadenza giornaliera, da eseguire nelle settimane 1, 5, 9 e 13. b) valutazione clinica della miotonia (handgrip, orbicolare oculare); da effettuare alla visita iniziale e alla settimana 6, 10 e 14. c) valutazione della miotonia mediante dinamometro (handgrip), mediante calcolo tempo di rilassamento dal 90% al 5% della forza massima mediante un software specifico; da effettuare alla visita iniziale e alla settimana 6, 10 e 14. d) Individualized Neuromuscular Quality of Life (Sansone at al., 2012); da effettuare alla visita iniziale e alla settimana 6, 10 e 14. e) SF-12; da effettuare alla visita iniziale e alla settimana 6, 10 e 14

E.5.2.1

Timepoint(s) of evaluation of this end point

a) 1, 5, 9 and 13 weeks. b, c, d, e) 6, 10 and 14 weeeks.

a) 1, 5, 9 e 13 settimane. b, c, d, e) 6, 10 e 14 settimane.

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

Yes

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)

Yes

F.1.3.1

Number of subjects for this age range:

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 2020-11-05.

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)

Treatment and care based on normal clinical practice

Trattamento e assistenza secondo normale pratica 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

2015-11-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-10

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

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Orphan Designation Number:
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