E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with MuSK Antibody Positive Myasthenia Gravis |
Pazienti affetti da Miastenia Grave MuSK-positiva |
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E.1.1.1 | Medical condition in easily understood language |
Patients with MuSK Antibody Positive Myasthenia Gravis |
Pazienti affetti da Miastenia Grave MuSK-positiva |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062976 |
E.1.2 | Term | Neuromuscular weakness |
E.1.2 | System Organ Class | 100000004859 |
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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 characterize the overall safety and tolerability of amifampridine compared with placebo in patients with MuSK-MG |
Caratterizzare la sicurezza globale e la tollerabilità di amifampridina rispetto al placebo in pazienti con MuSK -MG |
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E.2.2 | Secondary objectives of the trial |
• To assess the clinical efficacy of amifampridine compared with placebo in patients with MuSK-MG based on improvement in the Myasthenia Gravis Composite (MGC) scale scores. • To assess the clinical efficacy of amifampridine compared with placebo by: o Neurological Institute Carlo Besta-Myasthenia Gravis (NICB-MG) scale; o Fatigue measured by Fatigue Severity Scale (FSS);
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• Valutare l’efficacia clinica dell’amifampridina rispetto al placebo in pazienti affetti da MuSK-MG mediante: a) scala di valutazione “Myasthenia Gravis Composite” (MGC), scala di valutazione dell’Istituto Neurologico C. Besta (NICB-MG) e scala “Quantitative Myasthenia Gravis” (QMG) • Valutare la fatica mediante la “Fatigue Severity Scale” (FSS) • Valutare l’effetto sull’attività di vita quotidiana mediante la scala “Myasthenia Gravis-Specific Activities of Daily Living (MG-ADL) • Valutare la qualità della vita mediante la scala “Myasthenia Gravis-Quality of Life (MG-QoL)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent after the nature of the study has been explained and before the start of any research-related procedures. 2. Male or female ≥18 years of age. 3. Positive serologic test for anti-MuSK antibodies as confirmed at Screening. 4. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV at Screening. 5. Myasthenia Gravis Composite (MGC) score equal or greater than 9 points is required at Screening. 6. Need of symptomatic treatment in order to improve muscle performance. 7. Patients undergoing immunosuppressive treatments may be included, but they must remain on stable treatment during the 70-day minimum study period. 8. Patients receiving steroids should not have any modification of drug regimen in the previous month before Screening. 9. Patients receiving immunosuppressive drugs (e.g. azathioprine, cyclophosphamide, methotrexate) should not have any modification of drug regimen in the previous 3 months before Screening. 10. Patients receiving immunomodulatory treatment (e.g. plasma exchange [PE], therapeutic plasma exchange [TPE], intravenous immunoglobulin G [IVIG]) should not have any treatment in the previous 3 weeks before Screening. 11. Female patients of childbearing potential must have a negative pregnancy test (serum human chorionic gonadotropin [HCG]). All patients must practice an effective, reliable and medically approved contraceptive regimen during the study and for up to 5 months following discontinuation of treatment. 12. Ability and availability to participate in the study for at least 70 days based on overall health of the patient and disease prognosis, as applicable, in the opinion of the investigator, and able to comply with all requirements of the protocol, including completion of study questionnaires.
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1. Intenzione a partecipare e capacità nel fornire un consenso informato dopo adeguata spiegazione dello scopo dello studio e prima dell’inizio di qualsiasi procedura prevista dallo studio. 2. Sesso maschile e femminile, di età ≥18 anni. 3. Test serologico positivo per la ricerca degli anticorpi anti-MuSK, confermato allo screening 4. Classe clinica da II a IV allo screening (secondo la Classificazione della Myasthenia Gravis Foundation of America - MGFA). 5. Punteggio MGC (Myasthenia Gravis Composite) ≥ 9 punti allo screening. 6. Necessità di trattamento sintomatico per migliorare la performance muscolare. 7. Pazienti sottoposti a terapia immunosoppressiva possono essere inclusi, ma il dosaggio della terapia deve rimanere stabile durante il periodo minimo di studio di 70 giorni. 8. Nel caso di pazienti in terapia steroidea, il dosaggio dello steroide non deve essere modificato per il mese precedente lo screening. 9. La terapia immunosoppressiva (i.e. azatioprina, ciclofosfamide e metrotrexate) non deve essere modificata per i tre mesi precedenti lo screening. 10. Plasmaferesi o immunoglobuline endovena ad alte dosi non devono essere somministrate nelle tre settimane precedenti lo screening. 11. Le pazienti in età fertile dovranno avere un test di gravidanza negativo; tutti i pazienti dovranno seguire una pratica contraccettiva efficace ed approvata per tutta la durata dello studio e per cinque mesi dopo la sospensione del trattamento. 12. Disponibilità e capacità di partecipazione allo studio per almeno 70 giorni in base alle condizioni generali di salute del paziente e prognosi della malattia, e capacità ad attenersi a quanto previsto dal protocollo incluso il completamento dei questionari.
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E.4 | Principal exclusion criteria |
1. Hypersensitivity to the active substance, or to any of the excipients listed. 2. Epilepsy. 3. Uncontrolled asthma. 4. Concomitant use with sultopride. 5. Concomitant use with medicinal products with a narrow therapeutic window. 6. Concomitant use with medicinal products with a known potential to cause QTc prolongation. 7. Patients with congenital QT syndromes. 8. History of thymectomy within 12 months before Screening. 9. Weakness only affecting ocular or peri-ocular muscles (MGFA Class I). 10. MG crisis at Screening (MGFA Class V). 11. An electrocardiogram (ECG) within 6 months before starting treatment that shows clinically significant abnormality(ies), in the opinion of the investigator. 12. Breastfeeding or pregnant at Screening or planning to become pregnant (self or partner) at any time during the study. Male patients with breastfeeding partners are not excluded from the study. 13. Any systemic bacterial or other infection, which is clinically significant in the opinion of the investigator and has not been treated with appropriate antibiotics. 14. Use of PE, TPB, and/or IVIG within 3 weeks before Screening. 15. Use of rituximab within 6 months before Screening. 16. Treatment with an investigational drug (other than amifampridine), device, or biological agent within 30 days before Screening or while participating in this study. 17. Any medical condition that, in the opinion of the investigator, might interfere with the patient’s participation in the study, poses any added risk for the patient, or confounds the assessment of the patients. 18. History of drug allergy to any pyridine-containing substances or any amifampridine excipient(s).
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1. Ipersensitività alla sostanza attiva o ad uno degli eccipienti elencati. 2. Epilessia 3. Asma non controllata. 4. Uso concomitante di sultopride. 5. Uso concomitante di medicinali con ristretta finestra terapeutica. 6. Uso concomitante di medicinali potenzialmente noti per causare prolungamento dell'intervallo QTc. 7. Pazienti con sindrome QT congenita. 8. Timectomia nei 12 mesi precedenti lo screening 9. Miastenia ad interessamento esclusivamente oculare (MGFA Classe I) 10. Crisi miastenica allo screening (MGFA Classe V). 11. Riscontro ECG, effettuato nei 6 mesi precedenti l’inizio dello studio, di anomalie clinicamente significative, secondo giudizio del PI. 12. Stato di gravidanza o allattamento allo screening o desiderio di gravidanza (del paziente o del partner) in qualsiasi momento durante lo studio. 13. Riscontro di qualsiasi infezione batterica o di altra natura, ritenuta clinicamente significativa dal PI e non trattata in modo adeguato. 14. Utilizzo di plasmaferesi, immunoglobuline ad alte dosi o TPB nelle 3 settimane precedenti lo screening. 15. Uso di Rituximab nei 6 mesi precedenti lo screening. 16. Trattamento con farmaco, agente biologico o strumento sperimentale (diverso dall’ amifampridina), nei 30 giorni precedenti lo screening o durante lo studio. 17. Qualsiasi condizione medica che, a giudizio del PI, possa interferire con la partecipazione allo studio, comporti rischi aggiuntivi per il paziente, o infici la valutazione dei pazienti inclusi nello studio. 18. Storia di allergia a qualsiasi farmaco contenente derivati piridinici o a eccipienti della amiframpridina.
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of TEAEs and SAEs in MuSK-MG patients treated with amifampridine as compared with placebo; |
La sicurezza verrà valutata attraverso l’incidenza di eventi avversi legati al farmaco ed eventi avversi gravi. Verranno valutati anche i segni vitali, ECG, esami di laboratorio, e le terapie concomitanti. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
during all treatment |
durante tutto il trattamento |
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E.5.2 | Secondary end point(s) |
• Difference in MGC of 3 points from baseline; and • Proportion of patients with at least a 3-point reduction in the MGC total score from baseline. • Difference in the NICB-MG total score; • Difference in the FSS mean score; • Difference in the MG-ADL of at least 2 points from baseline; • Difference in the MG-QoL 15 total score; and • Difference in the QMG score.
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• Differenza di punteggio nella scala MGC; • Proporzione di pazienti con una riduzione di punteggio di almeno 3 punti nella scala MGC rispetto al baseline. • Differenza di punteggio nella scala NICB-MG; • Differenza di punteggio nella scala FSS; • Differenza di punteggio nella scala MG-ADL; • Differenza di punteggio nella scala MG-QoL 15; • Differenza di forza e affaticamento misurata con la scala QMG.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
at the end of the study |
al termine dello studio |
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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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | Yes |
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 | 2 |
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |