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    Summary
    EudraCT Number:2017-002631-42
    Sponsor's Protocol Code Number:MS700568_0022
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-02-02
    Trial results View 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 ConcernedSpain - AEMPS
    A.2EudraCT number2017-002631-42
    A.3Full title of the trial
    A 2-year prospective study to evaluate the onset of action of Mavenclad® in subjects with highly active relapsing multiple sclerosis
    Estudio prospectivo, de dos años de duración, para evaluar el inicio de acción de Mavenclad® en sujetos con esclerosis múltiple recidivante de elevada actividad
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Research Study for People with Relapsing Multiple Sclerosis
    Un Ensayo Clinico para Sujetos con Esclerosis Múltiple Recidivante
    A.4.1Sponsor's protocol code numberMS700568_0022
    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 SponsorMerck KGaA
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication Center Merck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+3491 3913443
    B.5.5Fax number+496151722000
    B.5.6E-mailservice@merckgroup.com
    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 Mavenclad®
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono Europe Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCladribine
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCLADRIBINE
    D.3.9.1CAS number 4291-63-8
    D.3.9.2Current sponsor codeEMD280922
    D.3.9.3Other descriptive name2-chloro-2’-deoxyadenosine (2-CdA)
    D.3.9.4EV Substance CodeSUB06635MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsing multiple sclerosis
    Esclerosis múltiple recidivante
    E.1.1.1Medical condition in easily understood language
    Relapsing multiple sclerosis
    Esclerosis múltiple recidivante
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the onset of action of Mavenclad®in subjects with highly active relapsing multiple sclerosis (RMS).
    Determinar el inicio de acción de Mavenclad® en sujetos con esclerosis múltiple recidivante (relapsing multiple sclerosis, RMS) de elevada actividad
    E.2.2Secondary objectives of the trial
    To assess the effect of Mavenclad® on different immune system
    composites in particular cell subtypes count and repopulation
    Evaluar el efecto de Mavenclad®sobre diferentes componentes del sistema inmunitario, en especial, sobre el número y la repoblación de distintos subtipos celulares
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1- OCT Substudy : This sub-study explores the concept of using OCT as a structural biomarker of disease development in MS patients. The goal of this exploratory sub-study is to investigate the axonal degeneration in subjects enrolled
    into the trial, by measuring the RNFL thickness with OCT.
    The three objectives of this exploratory sub-study are:
    -To describe the axonal degeneration at 12 and 24 months compared to baseline
    -To describe the correlation of axonal degeneration with ‘traditional’ MS related assessments (e.g. MRI, EDSS…)
    -To describe changes in RNFL thinning over time

    2- DTI and fMRI Sub-study: This sub-study explores the concept of using DTI and fMRI as a structural biomarker of disease
    that are specific for brain tissue injury and repair.
    The goal of this exploratory sub-study is to investigate the brain structural and functional changes in subjects enrolled into the trial, by measuring DTI and fMRI over time.
    The three objectives of this exploratory sub-study are:
    -To describe the changes in DTI and fMRI at 12 and 24 months compared to baseline
    -To describe the correlation of DTI and fMRI with ‘traditional’ MS related assessments (e.g. MRI, EDSS…)
    - To describe changes in DTI and fMRI over time

    3 CSF Biomarker Sub-study: Validated biomarkers will help to define an optimal cladribine treatment response in MS and thus be of considerable value for taking treatment decisions and ensuring continued benefit from cladribine therapy. The candidate biomarkers have been selected on basis of evidences from literature.
    The goal of this exploratory sub-study is to investigate the surrogate marker in subjects enrolled into the
    trial, by measuring CSF biomarkers over time.
    The objectives of this exploratory sub-study are:
    -To describe the changes in CSF biomarkers at 12 and 24 months compared to baseline
    - To describe the correlation of biomarkers with ‘traditional’ MS related assessments (e.g. MRI, EDSS…)
    - To describe changes in biomarker over time

    4- Blood Biomarker Sub-study
    The goal of this exploratory sub-study is to investigate the surrogate marker in patients enrolled into the trial, by measuring blood biomarkers over time.
    The objectives of this exploratory sub-study are:
    -To describe changes in biomarker over time
    -To describe the correlation of biomarkers with ‘traditional’ MS related assessments (e.g. MRI, EDSS)
    1- Subestudio de OCT: Este subestudio va a explorar el concepto teórico del empleo de la OCT como biomarcador estructural del desarrollo de la enfermedad en pacientes con esclerosis múltiple. El objeto de este subestudio exploratorio es investigar la degeneración axonal en los sujetos participantes en el ensayo, mediante la medición del grosor de la capa de fibras nerviosas retinianas (RNFL) por OCT.
    Este subestudio exploratorio tiene tres objetivos, que son:
    - Describir la degeneración axonal a los 12 y 24 meses en comparación con el basal
    - Describir la correlación de la generación axonal con las evaluaciones “tradicionales” de la esclerosis múltiple (ej.: resonancia magnética [RMI], EDSS [escala ampliada del estado de discapacidad], etc.)
    - Describir los cambios en el adelgazamiento del RNFL a lo largo del tiempo

    2- Subestudio de obtención de imágenes por tensor de difusión (DTI) y resonancia magnética funcional (fMRI): Este subestudio va a explorar el concepto teórico de utilizar la DTI y la fMRI como biomarcadores estructurales específicos de la lesión del tejido cerebral y de su reparación.
    - El objeto de este subestudio exploratorio es investigar los cambios estructurales y funcionales en cerebro de los sujetos participantes en el ensayo, mediante su medición con DTI y fMRI a lo largo del tiempo.
    Este subestudio exploratorio tiene tres objetivos, que son:
    - Describir los cambios en DTI y fMRI a los 12 y 24 meses en comparación con el basal
    - Describir la correlación de DTI y fMRI con las evaluaciones “tradicionales” de la esclerosis múltiple (ej., MRI, EDSS, etc.)
    - Describir los cambios en DTI y fMRI a lo largo del tiempo

    3- Subestudio de biomarcadores en líquido cefalorraquídeo (CSF): Ciertos biomarcadores validados podrán ayudar a definir la respuesta óptima al tratamiento con cladribina en la esclerosis múltiple, siendo, en consecuencia, de considerable valor para la adopción de decisiones acerca del tratamiento y para comprobar que se mantiene el beneficio de la cladribina. Los posibles biomarcadores se han elegido en función de los datos de la literatura.
    El objeto de este subestudio exploratorio es investigar dichos marcadores indirectos en los sujetos participantes en el ensayo, mediante la medición de los biomarcadores en CSF a lo largo del tiempo.
    Los objetivos de este subestudio exploratorio son:
    - Describir los cambios en los biomarcadores en CSF a los 12 y 24 meses en comparación con el basal
    - Describir la correlación de los biomarcadores con las evaluaciones “tradicionales” de la esclerosis múltiple (ej. MRI, EDSS, etc.)
    - Describir los cambios en los biomarcadores a lo largo del tiempo

    4- Subestudio de biomarcadores en sangre
    El objeto de este subestudio exploratorio es investigar dichos marcadores indirectos en los sujetos participantes en el ensayo, mediante la medición de los biomarcadores en sangre a lo largo del tiempo.
    Los objetivos de este subestudio exploratorio son:
    - Describir los cambios en los biomarcadores a lo largo del tiempo
    - Describir la correlación de los biomarcadores con las evaluaciones “tradicionales” de la esclerosis múltiple (ej. MRI, EDSS, etc.)
    E.3Principal inclusion criteria
    •Male or female subjects >= 18 years old
    •Highly active RMS as defined by:
    -One relapse in the previous year and at least 1 T1 Gd+ lesion or 9 or more T2 lesions, while on therapy with other disease modifying drugs (DMDs)
    -Two or more relapses in the previous year, whether on DMD treatment or not
    •EDSS score <=5.0
    - Varones o mujeres >= 18 años
    - Esclerosis múltiple recidivante de elevada actividad, definida por:
    - Una recidiva en el año anterior y al menos una lesión en T1 Gd+ o bien 9 o más lesiones en T2 durante el tratamiento con otros fármacos modificadores de la esclerosis múltiple (disease modifying drugs, DMD)
    - Dos o más recidivas en el año anterior, con o sin tratamiento con modificadores de la esclerosis múltiple
    - Puntuación EDSS <=5,0
    E.4Principal exclusion criteria
    •Previous exposure to drugs such as fingolimod, natalizumab, alemtuzumab, mitoxantrone and ocrelizumab
    •Positive hepatitis C or hepatitis B surface antigen test and/or hepatits B core antibody test for IgG and/or IgM
    •Current or previous history of immune deficiency disorders including a positive human immunodeficiency virus (HIV) result
    •Currently receiving immunosuppressive or myelosuppressive therapy with, e.g., monoclonal antibodies, methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic use of corticosteroids
    •History of tuberculosis , presence of active tuberculosis, or latent tuberculosis
    •Evidence or suspect of PML in MRI
    •Active malignancy or history of malignancy
    • lymphocyte count not within normal limits of the local hospital lab before initiation of first treatment course
    - Exposición previa a ciertos fármacos, como fingolimod, natalizumab, alemtuzumab, mitoxantrona y ocrelizumab
    - Resultado positivo en las pruebas de hepatitis C o del antígeno de superficie del virus de la hepatitis B y/o de anticuerpos contra el antígeno central del virus de la hepatitis B (IgG y/o IgM)
    - Presencia o antecedentes de trastornos por deficiencias inmunitarias, lo que incluye el resultado positivo al virus de la inmunodeficiencia humana (human immunodeficiency virus, HIV)
    - En tratamiento inmunosupresor o mielosupresor actual con, por ejemplo, anticuerpos monoclonales, metotrexato, ciclofosfamida, ciclosporina o azatioprina, o uso prolongado de corticosteroides
    - Antecedentes de tuberculosis, presencia de tuberculosis activa o tuberculosis latente
    - Evidencia o sospecha de leucoencefalopatía multifocal progresiva (progressive multifocal leukoencephalopathy, PML) en la resonancia magnética
    - Neoplasia maligna activa o antecedentes de cancer
    -Recuento de linfocitos fuera de los límites normales del laboratorio del hospital local antes del inicio del primer ciclo de tratamiento
    E.5 End points
    E.5.1Primary end point(s)
    •Difference in the counts of combined unique active (CUA) MRI lesions
    - Diferencia en el número de lesiones activas únicas combinadas (combined unique active, CUA) observadas mediante resonancia magnética
    E.5.1.1Timepoint(s) of evaluation of this end point
    •At the end of 6 months compared to baseline
    - Al cabo de 6 meses en comparación con el valor basal
    E.5.2Secondary end point(s)
    •Characterization of immune cell subsets count
    - Determinación del número de las subpoblaciones de células inmunitarias
    E.5.2.1Timepoint(s) of evaluation of this end point
    •At the end of 3, 6, 12, 15, 18 and 24 months compared to baseline
    - Al cabo de 3, 6, 12, 15, 18 y 24 meses, en comparación con el valor basal
    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 No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Canada
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Ireland
    Israel
    Italy
    Netherlands
    Norway
    Spain
    Sweden
    Switzerland
    United Kingdom
    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
    The end of the trial is defined as the last subject’s End of Trial visit.
    El final del ensayo se define como la ultima visita del ensayo del ultimo sujeto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months9
    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.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 300
    F.1.3Elderly (>=65 years) No
    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 No
    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 No
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 280
    F.4.2.2In the whole clinical trial 300
    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)
    Upon completion of study, subjects will be offered the opportunity of enrolling into an Extension study for a further 2 years (i.e., until 4 years from first treatment year course). A separate protocol will be followed for the Extension study.
    Patients who will not roll over to the extension study will return to their standard of care treatment.
    Una vez finalizado el estudio, se ofrecerá a los sujetos la opción de participar en un estudio de Extensión durante 2 años más (esto es, hasta transcurridos 4 años desde su primer ciclo anual de tratamiento). Para dicho estudio de Extensión se seguirá otro protocolo.
    Los pacientes que no pasen al estudio de Extensión volverán a su tratamiento habitual.
    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 Decision2018-03-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-10-08
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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