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 |
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E.1.1.1 | Medical condition in easily understood language |
Multiple sclerosis |
Sclerosi multipla |
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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 |
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E.1.3 | Condition being studied is a rare disease | No |
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 |
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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. |
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E.2.3 | Trial contains a sub-study | No |
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.
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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.
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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.
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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) |
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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 |
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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 |
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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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
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 | 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 2 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 2 |