Clinical Trials Register

Summary
EudraCT Number:	2014-004650-34
Sponsor's Protocol Code Number:	GR-2011-02348985
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

2014-004650-34

A.3

Full title of the trial

Neuromodulation strategies to enhance the effects of gait rehabilitation in multiple sclerosis patients with cerebellar ataxia

A.3.1

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

New strategies for diagnostic, therapeutic and clinical care in neurological diseases

Nuove strategie per la diagnosi, la terapia e la gestione medica nelle malattie neurologiche

A.3.2

Name or abbreviated title of the trial where available

New strategies in neurological diseases

Nuove strategie nella patologie neutorologiche

A.4.1

Sponsor's protocol code number

GR-2011-02348985

A.5.4

Other Identifiers

Name:

New strategies

Number:

GR-2011-20348985

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	IRCCS FONDAZIONE ISTITUTO NEUROLOGICO NAZIONALE C. MONDINO
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
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	IRCCS Fondazione Istituto Neurologico Nazionale C. Mondino
B.5.2	Functional name of contact point	Clinical Trial Center
B.5.3	Address:
B.5.3.1	Street Address	Via Mondino, 2
B.5.3.2	Town/ city	Pavia
B.5.3.3	Post code	27100
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390382380818
B.5.5	Fax number	+390382380448
B.5.6	E-mail	cinzia.fattore@mondino.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	FAMPYRA - 10 MG - COMPRESSA A RILASCIO PROLUNGATO - USO ORALE - FLACONE (HDPE) 56 COMPRESSE (4 FLACONI DA 14)
D.2.1.1.2	Name of the Marketing Authorisation holder	BIOGEN IDEC 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.3.4	Pharmaceutical form	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.3.8	INN - Proposed INN	FAMPRIDINA
D.3.9.1	CAS number	504-24-5
D.3.9.2	Current sponsor code	4-AP
D.3.9.3	Other descriptive name	4-aminopyridine
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	10
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Multiple sclerosis with cerebellar ataxia

Sclerosi multipla con atassia cerebellare

E.1.1.1

Medical condition in easily understood language

Multiple sclerosis

Sclerosi multipla

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	20.1
E.1.2	Level	PT
E.1.2	Classification code	10028245
E.1.2	Term	Multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety and clinical effectiveness of cerebellar TBS and 4-aminopiridine for enhancing the effects of gait rehabilitation

Valutare la sicurezza e l'efficacia clinica della TBS cerebellare e della 4-aminopiridina nell'incrementare gli effetti della riabilitazione del cammino

E.2.2

Secondary objectives of the trial

To describe the behavioural changes in motor control and learning induced by cerebellar iTBS and by 4-AP, and to detect the associated changes in the cerebello-cortical circuits in multiple sclerosis (MS) patients with CGA

Descrivere i cambiamenti comportamentali nel controllo motorio e nell¿apprendimento indotti dall¿iTBS cerebellare e dalla 4-AP a rilascio prolungato per rilevare i cambiamenti associati nei circuiti cerebello-corticali.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Aged 18–70 years,
With clinically defined multiple sclerosis (McDonald 2010),
Able to complete two trials of the timed 25-foot walk (T25FW)
EDSS between 4 and 6,
International Cooperative Ataxia Rating Scale (ICARS) walking capacities score =2,
Pyramidal Functional System Score (FSS) =2.

Età 18–70 anni,
Diagnosi di Sclerosi Multipla (McDonald 2010),
Pazienti in grado di completare due prove del test dei 25 passi(T25FW),
EDSS compreso tra 4 e 6,
International Cooperative Ataxia Rating Scale (ICARS) =2,
Pyramidal Functional System Score (FSS) =2.

E.4

Principal exclusion criteria

Onset of multiple sclerosis exacerbation within 90 days of screening,
A history of seizures a history of seizures or the presence of vascular, infectious or methabolic lesions of the cerebral cortex leading to symptomatic seizures,
Allergy to pyridine or tablet excipients
Patients treated with drugs containing 4-aminopyridine,
Any condition that would interfere with the conduct or interpretation of the study,
Contraindication to the use of the Transcranial Magnetic Stimulator,
Clinically significant abnormal laboratory values or electrocardiogram at screening,
Patients with impaired renal function mild, moderate or severe (creatinine cleareance <80 ml/min),
Patients treated with OCT2 inhibitors, for example cimetidine,
Women were excluded if they were pregnant, lactating or of childbearing potential and not using adequate birth control.

We set additional restrictions on changes in concomitant medications to avoid related changes in multiple sclerosis symptoms during the trial.

Esacerbazione della sclerosi multipla entro 90 giorni dallo screening,
Storia di crisi convulsive, o presenza di lesioni vascolari, infettive o metaboliche della corteccia cerebrale responsabili di crisi epilettiche sintomatiche,
Allergia alla piridina o agli eccipienti della compressa,
Pazienti trattati con farmaci contenenti 4-aminopiridina,
Ogni condizione che potrebbe interferire con l’interpretazione e la conduzione dello studio,
Controindicazioni all’utilizzo della Stimolazione Magnetica Transcranica,
Esami di laboratorio o ECG clinicamente significativi allo screening,
Pazienti con funzionalità renale compromessa (clearance della creatinina <80 ml/min),
Pazienti trattati con inibitori OCT2, per esempio cimetidina,
Donne gravide o in allattamento o fertili, che non utilizzano metodi adeguati per il controllo delle nascite.

Restrizioni addizionali riguardano i cambiamenti nei farmaci concomitanti assunti per evitare variazioni nella sintomatologia della sclerosi multipla durante il trial.

E.5 End points

E.5.1

Primary end point(s)

we expect to find a >21.43% difference between the treatment (baseline/end of treatment T25FT score ratio: mean 1.4, SD 0.17) and the placebo group (baseline/end of treatment T25FT score ratio: mean 1.1, SD 0.04).

Cambiamenti nella velocità del cammino (in piedi al secondo), valutata con il timed 25-foot walk (T25FW)

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the two-week experimental treatment period (day 14) with respect to baseline.

Giorno 14 dall'inizio del trattamento

E.5.2

Secondary end point(s)

changes of motor control and learning (saccades adaptation, gait analysis, ICARS, Ashworth score for spasticity, a lower extremity manual muscle test -LEMMT); Changes of fatigue (ocular motor fatigue task, Fatigue Severity Scale - FSS); Changes of functional disability and quality of life (12-item multiple sclerosis walking scale MSWS-12, Activities of Daily Living - ADL, Barthel index - BI, Functional Independence Measure - FIM, Multiple Sclerosis Quality of life inventory - MSQoL-54); Changes of cerebellar-thalamo-cortical inhibition (CBI), parieto-motor functional connection (PPC-M1) short intracortical inhibition (SICI) and intracortical facilitation (ICF), vestibular-spinal tract function (soleus EMG response); Changes of cognitive function (Paced Auditory Serial Addition Task - PASAT, Symbol Digit Modalities Test -SDMT, Controlled Oral Word Association Test, Nine-hole pegboard task).

Modifiche nel controllo motorio e nell'apprendimento; Variazioni nella valutazione della fatica; Variazioni nella disabilit¿ funzionale e nella qualit¿ di vita; Variazioni dell'inibizione cerebello-talamo-corticale, della connessione funzionale parieto-motoria, dell'inibizione breve intracorticale, della facilitazione intracorticale e della funzione del tratto vestibolo-spinale.; Variazioni della funzione cognitiva

E.5.2.1

Timepoint(s) of evaluation of this end point

The changes will be evaluated at the end of the two-week experimental treatment period (day 14), and at the end of the standard rehabilitation (day 28) and after another four week period (day 56) as follow-up. ; The changes will be evaluated at the end of the two-week experimental treatment period (day 14), and at the end of the standard rehabilitation (day 28) and after another four week period (day 56) as follow-up. ; The changes will be evaluated at the end of the two-week experimental treatment period (day 14), and at the end of the standard rehabilitation (day 28) and after another four week period (day 56) as follow-up. ; The changes will be evaluated at the end of the two-week experimental treatment period (day 14), and at the end of the standard rehabilitation (day 28) and after a

Giorno 14, 28 e 56 dall'inizio del trattamento; Giorno 14, 28 e 56 dall'inizio del trattamento; Giorno 14, 28 e 56 dall'inizio del trattamento; Giorno 14, 28 e 56 dall'inizio del trattamento; Giorno 14, 28 e 56 dall'inizio del trattamento

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

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

Yes

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.8.5.1

Number of sites anticipated in the EEA

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

At the end of the study the blinding will be broken and for patients showing a significant improvement in their walking ability will be considered with the competent authorities the possibility of treatment continuation.

Alla fine dello studio per i pazienti, che avranno tratto beneficio dal trattamento (miglioramento del cammino), sar¿ considerata con le Autorit¿ Competenti la possibilit¿ di continuare il trattamento.

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

2016-06-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-07

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

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