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    Summary
    EudraCT Number:2011-005021-48
    Sponsor's Protocol Code Number:TL011-RA-301
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-02-21
    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 number2011-005021-48
    A.3Full title of the trial
    A multicenter, double-blind, randomized, active controlled, parallelgroup
    study to evaluate the efficacy, safety, tolerability and
    pharmacodynamic profiles of TL011 infusions compared with MabThera®
    (rituximab) in subjects with severe, active rheumatoid arthritis treated
    with methotrexate (MTX)
    Estudio multicéntrico, doble ciego, aleatorizado, controlado con principio activo y de grupos paralelos, para evaluar los perfiles de eficacia, seguridad, tolerabilidad y farmacodinámica de TL011 en infusión IV, comparado con MabThera (rituximab) en sujetos con artritis reumatoide activa de grado severo tratados con metotrexato (MTX)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate and compare the efficacy, safety, tolerability and
    pharmacodynamic (biochemical and physiological effects of the drug) of
    TL011 and MabThera® (rituximab) in patients with severe, active
    rheumatoid arthritis treated with methotrexate (MTX)
    Un estudio para evaluar y comparar la eficacia, seguridad, tolerabilidad y farmacodinámica de TL011 y MabThera (rituximab) en sujetos con artritis reumatoide activa de grado severo tratados con metotrexato (MTX)
    A.3.2Name or abbreviated title of the trial where available
    ALTO
    A.4.1Sponsor's protocol code numberTL011-RA-301
    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 SponsorTeva Pharmaceutical Industries
    B.1.3.4CountryIsrael
    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 supportTeva Pharmaceutical Industries
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTeva Pharmaceutical Industries
    B.5.2Functional name of contact pointDr. Ronit Haviv
    B.5.3 Address:
    B.5.3.1Street Address12 Hatrufa St.
    B.5.3.2Town/ cityNetanya
    B.5.3.3Post code42504
    B.5.3.4CountryIsrael
    B.5.4Telephone number+97298361152
    B.5.5Fax number+97298361364
    B.5.6E-mailronit.haviv@teva.co.il
    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 No
    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 nameTL011
    D.3.2Product code TL011
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTL011
    D.3.9.2Current sponsor codeTL011
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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 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 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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 MabThera®, 100 mg Concentrado para solución para perfusión
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd.
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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 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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Sujetos adultos con artritis reumatoide (AR) activa de grado severo tratados con MTX
    E.1.1.1Medical condition in easily understood language
    artritis reumatoide (AR)
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Demostrar la equivalencia de la eficacia de TL011 en comparación con el producto de referencia, MabThera (rituximab), en sujetos con AR activa de grado severo tratados con MTX.
    E.2.2Secondary objectives of the trial
    Evaluar la farmacodinamia (FD), inmunogenia, seguridad y tolerabilidad de TL011 en comparación con MabThera (rituximab) en sujetos con AR activa de grado severo tratados con MTX.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. 18-80 años de edad (ambos incluidos) en la selección.
    2. Artritis reumatoide desde hace como mínimo 6 meses, definida según ACR 1987 (AR de comienzo en la edad adulta).
    3. Enfermedad activa, severa, seropositiva (FR en plasma de como mínimo 20 UI/mL y/o positividad de ACPA/anti-CCP), definida por 2 o más de los siguientes parámetros en los exámenes de la selección:
    ? Enfermedad activa, definida por la presencia de como mínimo 8 articulaciones con tumefacción y 8 con dolor a palpación (en la visita de selección).
    ? PCR en suero ?10 mg/L (1.0 mg/dL) y/o VSG (método de Westergren) ?28 mm por hora en la selección.
    4. Respuesta inadecuada o intolerancia a los FARME distintos del MTX y/o a los tratamientos con iTNF (1 o más).
    5. Tratamiento con MTX (10 a 25 mg/semana) durante como mínimo 12 semanas antes de la selección, con como mínimo 4 semanas antes de la selección a una dosis estable que deberá permanecer estable a lo largo del periodo del estudio (hasta la Semana 48).
    6. Voluntad y capacidad de otorgar el consentimiento informado por escrito antes de la práctica de los procedimientos del estudio.
    7. De potencial reproductor y utilizando (o haciendo que su pareja, del sexo que sea, utilice) un método anticonceptivo eficaz desde la selección y hasta 12 meses después de la última infusión (en este estudio, los métodos anticonceptivos aceptados son: esterilización quirúrgica, dispositivo intrauterino, anticonceptivos orales, parche anticonceptivo, anticonceptivos inyectables de larga duración, vasectomía de la pareja o método de doble barrera [preservativo o diafragma con espermicida]).
    E.4Principal exclusion criteria
    1. Enfermedad documentada de tipo reumático autoinmunitario o articular inflamatoria distinta de la artritis reumatoide (por ejemplo, artritis psoriásica o espondilitis anquilosante).
    2. Afectación sistémica importante secundaria a artritis reumatoide (por ejemplo, vasculitis, fibrosis pulmonar o síndrome de Felty) o enfermedad de clase funcional IV de la American Rheumatism Association (ARA).
    3. Hipersensibilidad a los principios activos, sus excipientes (citrato sódico, polisorbato 80, cloruro sódico, hidróxido sódico, ácido clorhídrico, agua para inyectables) y las proteínas murinas.
    4. Infección (viral, bacteriana o fúngica) activa no controlada que requiere tratamiento sistémico o infección clínicamente importante en la selección y/o el Día 1 (basal), o historia de infecciones recurrentes o crónicas o con procesos subyacentes que, a criterio del investigador, pudieran predisponer a los sujetos a infecciones graves.
    5. Síndrome de inmunodeficiencia conocido, lo que incluye unas inmunoglobulinas totales (IgG, IgA e IgM) por debajo del límite inferior de la normalidad (LIN).
    6. Positividad de la serología del virus de la inmunodeficiencia humana (VIH) (en caso de resultado positivo, deberá determinarse también el ARN del VIH) positividad del antígeno de superficie de la hepatitis B o positividad del antígeno de la hepatitis C (en caso de resultado positivo, deberá determinarse también el ARN del virus de la hepatitis C [VHC]).
    7. Antecedentes de cáncer en los 5 años anteriores a la selección (excepción hecha del carcinoma cutáneo basocelular que se ha resecado).
    8. Vacunación con vacunas de virus vivos menos de 4 semanas antes del Día 1 (basal) y/o programación de vacunación con virus vivos durante el período nuclear del estudio y/o el periodo previsible de depleción de linfocitos B.
    9. Uso de corticosteroides sistémicos orales/intravenosos/intramusculares
    ? Corticosteroides orales a una dosis mayor de 10 mg de prednisona al día (o una dosis equivalente de otros corticoides orales) dentro de las 4 semanas previas a la selección y entre la selección y el Día 1 (basal)
    O BIEN
    ? Corticosteroides orales a una dosis igual o menor de 10 mg de prednisona al día (o una dosis equivalente de otros corticoides orales) que no se ha mantenido estable en las 4 semanas previas a la selección y entre la selección y el Día 1 (basal).
    ? Uso de glucocorticoides intravenosos/intramusculares/intra-articulares o parenterales < 4 semanas antes de la selección.
    10. Uso de cualquier tratamiento citotóxico y de inmunosupresores (excepto la administración permitida de MTX) u otros FARME dentro de las 4 semanas antes de la selección o entre la selección y el Día 1 (basal).
    11. Uso previo de MabThera (rituximab) y/o participación en un ensayo clínico previo con el fármaco del estudio de investigación, TL011.
    12. Uso de iTNF o cualquier otro agente biológico para el tratamiento de enfermedades autoinmunitarias menos de 8 semanas antes del Día 1 (basal) o uso de Etanercept® y Anakinra® menos de 4 semanas antes del Día 1.
    13. Participación en un ensayo clínico previo y/o uso de un fármaco en investigación en el plazo de los 90 días antes de la selección.
    14. Enfermedad médica o quirúrgica clínicamente importante o inestable que, a criterio del Investigador, pudiera dificultar la participación segura y completa del sujeto en el estudio, tal como: enfermedad cardiovascular (incluida la insuficiencia cardíaca severa de clase IV de la New York Heart Association [NYHA] o enfermedad cardíaca severa no controlada), pulmonar, hepática, renal o neurológica en su determinación mediante historia médica, exploración física, análisis de laboratorio, radiografía de tórax o ECG.
    15. Probabilidad de no cumplimiento o de falta de colaboración durante el estudio, a criterio del Investigador.
    16. Antecedentes de tuberculosis, tuberculosis latente estudiada de acuerdo a las normativas locales, y/o radiografía de tórax positiva para tuberculosis en la selección o en los 6 meses previos.
    17. Mujer embarazada, en lactancia o que pretende quedarse embarazada durante el estudio o en el plazo de los 12 meses siguientes a la última infusión.
    18. Antecedentes de y/o presencia actual de consumo de drogas y/o alcoholismo
    E.5 End points
    E.5.1Primary end point(s)
    Criterio de valoración principal de la eficacia:
    Porcentaje de sujetos (%) que cumplen los criterios ACR20, que se definen como una mejoría de como mínimo el 20% frente a los valores pretratamiento
    E.5.1.1Timepoint(s) of evaluation of this end point
    Semana 24
    E.5.2Secondary end point(s)
    ACR20, ACR50, ACR70
    E.5.2.1Timepoint(s) of evaluation of this end point
    Semana 24 y 48
    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 Yes
    E.6.8Bioequivalence Yes
    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 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 No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Bulgaria
    Czech Republic
    Georgia
    Germany
    Hungary
    Macedonia, the former Yugoslav Republic of
    Poland
    Romania
    Russian Federation
    Serbia
    Spain
    Ukraine
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months21
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months21
    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: 354
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 190
    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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 228
    F.4.2.2In the whole clinical trial 544
    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)
    Después de completar el período principal del estudio (24 semanas en total, que incluye un período de 2 semanas de tratamiento y 22 semanas de seguimiento) se hará un seguimiento de los pacientes por un período adicional de 24 semanas, incluyendo aquellos que necesiten un nuevo ciclo de tratamiento en la semana 24 (según criterio del Investigador médico).
    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 Decision2012-05-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-09
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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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
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