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    Summary
    EudraCT Number:2017-004703-51
    Sponsor's Protocol Code Number:COMB157G2399
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-10-25
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2017-004703-51
    A.3Full title of the trial
    An open-label, single arm, multi-center extension study evaluating long-term safety, tolerability and effectiveness of ofatumumab in subjects with relapsing multiple sclerosis
    Estudio de extensión abierto, de brazo único y multicéntrico, para
    evaluar la seguridad, tolerabilidad y eficacia a largo plazo de
    ofatumumab, en pacientes con esclerosis múltiple que cursa con
    brotes
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Long-term safety, tolerability and effectiveness study of ofatumumab in subjects with relapsing multiple sclerosis
    Estudio de extensión abierto, para evaluar la seguridad, tolerabilidad y eficacia a largo plazo de ofatumumab en pacientes con EM que cursa con brotes
    A.4.1Sponsor's protocol code numberCOMB157G2399
    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 SponsorNovartis Farmacéutica, S.A
    B.1.3.4CountrySpain
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica, S.A
    B.5.2Functional name of contact pointTrial Monitoring Organization (TMo)
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number34933064464
    B.5.6E-maileecc.novartis@novartis.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 Arzerra
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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 nameofatumumab
    D.3.2Product code OMB157
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOFATUMUMAB
    D.3.9.1CAS number 679818-59-8
    D.3.9.4EV Substance CodeSUB25221
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Yes
    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
    D.8.3Pharmaceutical form of the placeboSolution for injection in pre-filled syringe
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple sclerosis
    Esclerosis múltiple
    E.1.1.1Medical condition in easily understood language
    Multiple sclerosis
    Esclerosis múltiple
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10048393
    E.1.2Term Multiple sclerosis relapse
    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
    Evaluate the long-term safety and tolerability of ofatumumab 20 mg sc once every 4 weeks in subjects with relapsing MS from the first dose of ofatumumab
    Evaluar la seguridad y tolerabilidad a largo plazo de 20 mg de ofatumumab, administrados por vía subcutánea (s.c.) una vez cada 4 (c4) semanas en pacientes con EM que cursa con brotes, desde la primera dosis de ofatumumab
    E.2.2Secondary objectives of the trial
    1. Describe long-term efficacy of ofatumumab 20 mg sc once every 4 weeks in subjects with relapsing MS (RMS) from the first dose of ofatumumab

    2. For subjects originally in COMB157G2301 and COMB157G2302 compare long-term outcomes in those who were immediately treated with ofatumumab versus delayed use of ofatumumab (i.e. after teriflunomide treatment in the COMB157G2301 and COMB157G2302 studies), by analyzing subjects according to their randomized treatment in COMB157G2301 and COMB157G2302

    3. For subjects randomized to teriflunomide in COMB157G2301 and COMB157G2302 and switched to ofatumumab in the COMB157G2399 compare both periods before and after the switch to ofatumumab

    4. Explore the long-term health outcomes in subjects with RMS treated with ofatumumab 20 mg sc once every 4 weeks from the first dose of ofatumumab
    1. Describir la eficacia a largo plazo de 20 mg de ofatumumab s.c., una vez cada c4 semanas, en pacientes con EM que cursa en brotes, desde la primera dosis de ofatumumab.
    2. Para los sujetos que provienen de los estudios COMB157G2301 y COMB157G2302, comparar los resultados a largo plazo de los que fueron tratados de forma inmediata con ofatumumab frente al uso retardado de ofatumumab (es decir, después de tratamiento con teriflunomida en los estudios COMB157G2301 y COMB157G2302), con el análisis de los pacientes según su tratamiento aleatorizado en el estudio COMB157G2301y COMB157G2302.
    3. Para los pacientes aleatorizados a teriflunomida en el estudio COMB157G2301y COMB157G2302 y que cambian a ofatumumab en el estudio COMB157G2399, comparar ambos periodos antes y después del cambio a ofatumumab.
    4. Explorar los resultados sanitarios a largo plazo en pacientes con EM que cursa en brotes tratados con 20 mg de ofatumumab s.c., una vez c4 semanas, desde la primera dosis de ofatumumab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects eligible for inclusion in this study must fulfill all of the following criteria:
    1. Must have participated in a Novartis MS study:
    • which dosed ofatumumab 20 mg sc every 4 weeks,
    • was an adult (≥ 18 years of age) study in RMS,
    • must have completed the study on study treatment (subjects that are on temporary drug interruption at the time of End of Study are considered completers).
    2. Written informed consent must be obtained before any assessment is performed
    Los pacientes elegibles para la inclusión en este estudio deben cumplir con todos los siguientes criterios:

    1. Haber participado en un estudio de EM de Novartis:
    -con dosis de 20 mg de ofatumumab s.c. administradas c4 semanas
    -que fuese un estudio en adultos (≥ 18 años) con EM que cursa en brotes,
    -que hayan completado el estudio y continúen en tratamiento con el fármaco del estudio
    2. Que puedan facilitar el consentimiento informado por escrito
    E.4Principal exclusion criteria
    1. Premature discontinuation from previous ofatumumab study or from study treatment in previous ofatumumab study
    2.Subjects that have had their previous ofatumumab study EOS > 6 months prior to screening and/or been given another MS DMT between EOS of previous study and screening of this study
    3.Less than 3.5-month washout of teriflunomide for subjects that will not complete the accelerated elimination procedure (AEP) prior to Day 1. Only applicable to subjects completing studies COMB157G2301 and COMB157G2302
    4.Subjects with a history of not being able or willing to cooperate or comply with study protocol requirements in the opinion of the Investigator
    5.Subjects that have any unresolved adverse event or condition from the previous study that necessitates temporary interruption of the study treatment, until such time as the event or condition has resolved (the subject will be monitored within the safety follow-up of the previous study during this time)
    6.Emergence of any clinically significant condition/disease during previous ofatumumab study in which study participation might result in safety risk for subjects
    7. Subjects with neurological findings consistent with PML or confirmed PML
    8.Subjects with active systemic bacterial, viral or fungal infections, or chronic infection (e.g. Acquired Immune Deficiency Syndrome (AIDS))
    9. Subjects that have developed or have had reactivation of syphilis or tuberculosis during previous ofatumumab study
    10. Subjects with severe hypoproteinemia e.g. nephrotic syndrome
    11. Any of the following abnormal laboratory values prior to Day 1:
    - Total or conjugated bilirubin (BIL) greater than 1.5 times the upper limit of normal (ULN) range
    - Alkaline phosphatase (ALP) greater than 2 times the ULN range
    - Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) greater than 3 times ULN
    - Any other clinically significant laboratory assessment as determined by the Investigator (e.g. significant anemia, neutropenia, thrombocytopenia, signs of impaired bone marrow function)
    1. Retirada prematura del estudio o del tratamiento del estudio previo de ofatumumab.
    2. Pacientes cuyo final del estudio (EOS) previo de ofatumumab haya tenido lugar > 6 meses antes de la selección y/o hayan recibido otro tratamiento modificador de la enfermedad (FAME) de la EM entre el EOS del estudio previo y la selección de este estudio.
    3. Periodo de lavado de menos de 3,5 meses de teriflunomida para pacientes que no completarán el procedimiento de eliminación acelerada (PEA) antes del día 1. Sólo aplicable para pacientes que completen los estudios COMB157G2301 y COMB157G2302.
    4. Pacientes que a criterio del investigador, presenten antecedentes de incapacidad o de no disposición para cooperar o cumplir con los requisitos del protocolo del estudio.
    5. Pacientes que presenten cualquier condición o acontecimiento adverso (AA) no resuelto del estudio previo que precise la interrupción temporal del tratamiento del estudio, hasta el momento en el que el acontecimiento o condición se haya resuelto (el paciente será controlado dentro del seguimiento de seguridad del estudio previo durante este periodo).
    6. Aparición de cualquier condición/enfermedad clínicamente significativa durante el estudio previo con ofatumumab, cuya participación en el estudio pudiese suponer un riesgo de seguridad para los pacientes
    7. Pacientes con hallazgos neurológicos coincidentes con leucoencefalopatía multifocal progresiva (LMP) o LMP confirmada.
    8. Pacientes con infecciones bacterianas, virales o fúngicas activas sistémicas o infección crónica (por ejemplo, síndrome de inmunodeficiencia adquirida (SIDA).
    9.Pacientes que hayan desarrollado o presentado reactivación de sífilis o tuberculosis durante el estudio previo de ofatumumab.
    10. Sujetos con hipoproteinemia severa, por ejemplo síndrome nefrótico.
    11. Cualquiera de los siguientes valores de laboratorio anormales antes del día 1:
    -Bilirrubina total o conjugada (BIL) mayor que 1.5 veces el límite superior del rango normal (LSN)
    -Fosfatasa alcalina (ALP) mayor que 2 veces el rango de ULN
    -Alanina aminotransferasa (ALT) / aspartato aminotransferasa (AST) más de 3 veces ULN
    - Cualquier otra evaluación de laboratorio clínicamente significativa según lo determine el investigador (por ejemplo, anemia significativa, neutropenia, trombocitopenia, signos de alteración de la función de la médula ósea)
    E.5 End points
    E.5.1Primary end point(s)
    • Proportion of subjects with adverse events
    • Proportion of subjects with laboratory, vital signs, or electrocardiogram (ECG) results meeting abnormal criteria
    • Proportion of subjects meeting predefined criteria in Columbia Suicide Severity Rating Scale (C-SSRS)
    -Proporción de sujetos con eventos adversos
    -Proporción de sujetos con resultados de laboratorio, signos vitales o electrocardiograma (ECG) que cumplen criterios anormales
    -Proporción de sujetos que cumplen con los criterios predefinidos en la escala de clasificación de gravedad del suicidio de Columbia (C-SSRS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    5 years after LPFV
    5 años después de LPFV
    E.5.2Secondary end point(s)
    • Annualized Relapse Rate (ARR)
    • Time to first relapse
    • Time to 3-month Confirmed Disability Worsening (3mCDW)
    • Time to 6-month Confirmed Disability Worsening (6mCDW)
    • Time to 6-month Confirmed Disability Improvement (6mCDI)
    • Time to 12-month Confirmed Disability Improvement (12mCDI)
    • Time to 24-month Confirmed Disability Improvement (24mCDI)
    • Time to 6-month Confirmed Disability Improvement (6mCDI) sustained until End of Study (EOS)
    • Change in Expanded Disability Status Scale (EDSS)
    • Time to 6-month confirmed 4-point worsening on Symbol Digit Modalities Test (SDMT)
    • Change in SDMT
    • Annualized T2 lesion rate
    • Number of T1 Gd-enhancing lesions per Magnetic Resonance Image (MRI) scan
    • Annual rate of change in brain volume
    • Change in NfL concentration in serum
    • Relationship between NFL and disease activity, disease course and treatment response
    • Patient Reported Outcomes (PRO)
    Tasa de recaída anualizada (ARR)
    • Tiempo para la primera recaída
    • Tiempo hasta 3 meses de empeoramiento confirmado de la discapacidad (3mCDW)
    • Tiempo hasta 6 meses de empeoramiento confirmado de discapacidad (6mCDW)
    • Tiempo hasta 6 meses de mejora confirmada de incapacidad (6mCDI)
    • Tiempo hasta la mejora confirmada de discapacidad de 12 meses (12mCDI)
    • Tiempo hasta la mejora confirmada de discapacidad de 24 meses (24mCDI)
    • Tiempo hasta 6 meses de Mejora confirmada de la discapacidad (6mCDI) sostenido hasta el final del estudio (EOS)
    • Cambio en la Escala de Estado de Discapacidad Expandida (EDSS)
    • Tiempo hasta 6 meses de empeoramiento confirmado de 4 puntos en Symbol Digit Modalities Test (SDMT)
    • Cambio en SDMT
    • Tasa de lesión T2 anualizada
    • Número de lesiones T1 Gd-enhancecing por imagen de resonancia magnética (MRI)
    • Tasa anual de cambio en el volumen cerebral
    • Cambio en la concentración de NfL en el suero
    • Relación entre la NFL y la actividad de la enfermedad, curso de la enfermedad y respuesta al tratamiento
    • Resultados informados por el paciente (PRO)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to 5 years
    Hasta 5 años
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    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 concerned19
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA210
    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
    Argentina
    Australia
    Austria
    Belgium
    Bulgaria
    Canada
    Croatia
    Czech Republic
    Denmark
    Estonia
    Finland
    France
    Germany
    Greece
    Hungary
    India
    Israel
    Italy
    Japan
    Latvia
    Lithuania
    Mexico
    Netherlands
    Norway
    Peru
    Poland
    Portugal
    Russian Federation
    Slovakia
    South Africa
    Spain
    Sweden
    Switzerland
    Taiwan
    Thailand
    Turkey
    United Kingdom
    United States
    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
    Study completion is defined as when the last subject finishes their Study Completion or End of Study visit and any repeat assessments associated with this End of Study visit have been documented and followed-up appropriately by the Investigator, or in the event of an early study termination decision, the date of that decision.
    La finalización del estudio se define cuando el último paciente completa el estudio o realiza la última visita y cualquier evaluación repetida asociada con esta visita al Final del estudio ha sido documentada y seguida adecuadamente por el investigador, o en el caso de una decisión de terminación temprana del estudio, la fecha de esa decisión.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    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: 2233
    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 state129
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1606
    F.4.2.2In the whole clinical trial 2233
    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)
    The investigator must provide follow-up medical care for all patients who are prematurely discontinued from the study, or must refer them back to their referring physician for appropriate care.
    El investigador debe proporcionar atención médica de seguimiento a todos los pacientes que se suspenden prematuramente del estudio, o debe derivarlos a su médico de referencia para recibir la atención adecuada.
    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 Decision2019-01-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-22
    P. End of Trial
    P.End of Trial StatusOngoing
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