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    Summary
    EudraCT Number:2015-003127-62
    Sponsor's Protocol Code Number:MuSK-001
    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:2017-03-17
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-003127-62
    A.3Full title of the trial
    A Randomized, Placebo-Controlled, Pilot Crossover Study to Evaluate the Effect of Amifampridine Phosphate
    (3,4-Diaminopyridine Phosphate) in Patients with MuSK Antibody Positive Myasthenia Gravis
    A Randomized, Placebo-Controlled, Pilot Crossover Study to
    Evaluate the Effect of Amifampridine Phosphate
    (3,4-Diaminopyridine Phosphate) in Patients with MuSK Antibody Positive Myasthenia Gravis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Placebo-Controlled Study to Evaluate the Effect of Amifampridine in Patients with MuSK Antibody Positive Myasthenia Gravis
    Studio randomizzato controllato con placebo per valutare l'effetto dell'amifampridina in pazienti affetti da Miastenia Grave Musk positivi
    A.3.2Name or abbreviated title of the trial where available
    MuSK-001
    MuSK-001
    A.4.1Sponsor's protocol code numberMuSK-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorFONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCatalyst Pharmaceutical Partners, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
    B.5.2Functional name of contact pointSERVIZIO RICERCA E SVILUPPO CLINICO
    B.5.3 Address:
    B.5.3.1Street AddressVIA CELORIA 11
    B.5.3.2Town/ cityMILANO
    B.5.3.3Post code20133
    B.5.3.4CountryItaly
    B.5.4Telephone number0223942321
    B.5.5Fax number0223943569
    B.5.6E-mailcrc@istituto-besta.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name FIRDAPSE - 10 MG - COMPRESSE - USO ORALE - BLISTER(ALU/PVC/PVDC) 100 X 1 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderBIOMARIN EUROPE LTD
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberORPHA218258
    D.3 Description of the IMP
    D.3.1Product nameAMIFAMPRIDINA
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAMIFAMPRIDINA
    D.3.9.2Current sponsor code0
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 80
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with MuSK Antibody Positive Myasthenia Gravis
    Pazienti affetti da Miastenia Grave MuSK-positiva
    E.1.1.1Medical condition in easily understood language
    Patients with MuSK Antibody Positive Myasthenia Gravis
    Pazienti affetti da Miastenia Grave MuSK-positiva
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10062976
    E.1.2Term Neuromuscular weakness
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary 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);
    • 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)
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    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.
    E.4Principal 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).
    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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    during all treatment
    durante tutto il trattamento
    E.5.2Secondary 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.
    • 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    at the end of the study
    al termine dello studio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA1
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial 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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 18
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women 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 2017-03-17. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 20
    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)
    If the treatment will provide clinical efficacy and no adverse events patients will continue treatment with aminefampridine
    In caso di dimostrata efficacia in assenza effetti collaterali i pazienti proseguiranno con il trattamento
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-10-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-14
    P. End of Trial
    P.End of Trial StatusOngoing
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