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    Summary
    EudraCT Number:2012-002535-28
    Sponsor's Protocol Code Number:R4-RA
    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:2015-07-10
    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 number2012-002535-28
    A.3Full title of the trial
    A Randomised, open labelled study in anti-TNFa inadequate responders to investigate the mechanisms for Response - Resistance to Rituximab versus Tocilizumab in RA (R4-RA)
    Estudio abierto y Randomizado en pacientes con artritis reumatoide y respuesta inadecuada a anti-TNFa, para investigar los mecanismos de Respuesta -Resistencia frente a Rituximab versus Tocilizumab. (R4-RA).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomised, open labelled study in anti-TNFa inadequate responders to investigate the mechanisms for Response - Resistance to Rituximab versus Tocilizumab in RA (R4-RA)
    Estudio abierto y Randomizado en pacientes con artritis reumatoide y respuesta inadecuada a anti-TNFa, para investigar los mecanismos de Respuesta -Resistencia frente a Rituximab versus Tocilizumab. (R4-RA).
    A.3.2Name or abbreviated title of the trial where available
    R4-RA
    A.4.1Sponsor's protocol code numberR4-RA
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN97443826
    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 SponsorJoint Research & Development Office (Barts and The London School of Medicine & Dentistry)
    B.1.3.4CountryUnited Kingdom
    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 supportECAM Clinical Academic Group Barts Health NHS Trust
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCTU clinical trial Unit- H Clinic Barcelona
    B.5.2Functional name of contact pointAnna Cruceta
    B.5.3 Address:
    B.5.3.1Street AddressMallorca
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08036
    B.5.3.4CountrySpain
    B.5.6E-mailacruceta@clinic.ub.es
    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 MabThera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameMabThera
    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.3.9.3Other descriptive nameMabThera
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2000
    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) Yes
    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.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 RoActemra
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameRoActemra
    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 INNtocilizumab
    D.3.9.1CAS number 375823-41-9
    D.3.9.3Other descriptive nameTOCILIZUMAB
    D.3.9.4EV Substance CodeSUB20313
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    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) Yes
    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
    Rheumatoid Arthritis
    Artritis Reumatoidea
    E.1.1.1Medical condition in easily understood language
    Rheumatoid Arthritis
    Artritis Reumatoidea
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10003268
    E.1.2Term Arthritis rheumatoid
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main aim of this project is to test the hypothesis that the presence or absence of specific synovial cellular and molecular signatures(B cells and B cell-associated signatures), assessed following a synovial tissue biopsy, will enrich for response / non-response to the B cell depleting anti-CD20 monoclonal antibody (mAb) Rituximab.

    The primary aim of this project is to show that in patients failing anti-TNF therapy, with a B cell poor synovial pathotype, Rituximab is inferior to Tocilizumab therapy.
    . Específicamente, conocer si una biopsia sinovial diagnóstica que muestra un ?prototipo rico/pobre en células B? define unos subgrupos de enfermos respondedores/resistentes que permitan la estratificación de los pacientes y ayuden a racionalizar la selección de los fármacos biológicos.
    E.2.2Secondary objectives of the trial
    In addition to the primary objective previously stated, we will address the following questions:
    1) Can a diagnostic synovial biopsy showing a B-cell ?rich/poor pathotype? define specific disease responsive/resistant subsets for patient stratification and help rationalize biologic drug choice?
    2) Is clinical response associated with inhibition of B cell-linked pathways within the synovium and dependent on local B cell lineage depletion?
    3) Is survival of auto-reactive B cells within ?protected? synovial niches responsible for B-cell joint re-population and disease resistance-relapse?
    ¿1) puede una muestra de la biopsia sinovial diagnóstico una b-célula "rich/poor pathotype" definir subgrupos de respondedores-resistentes para la estratificación de los pacientes y ayudar a racionalizar la elección del fármaco biológico?
    ¿2) está la respuesta clínica asociada a la inhibición de las vías de la célula de B- de la membrana sinovial y es dependiente del la poca producción de células B locales?
    ¿3) es la supervivencia de las células B auto-reactivas responsable de la repoblación conjunta de células B y resistencia-recidiva de los nichos de enfermedad sinovial ?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients will be recruited with active RA:
    1. Patients who have failed anti-TNF therapy (inadequate responders ? ir). Note: this includes patients that have failed anti-TNF therapy because of reactions.
    2. Who are eligible for Rituximab therapy according NICE guidlines*
    3. Patients should be receiving a stable dose Methotrexate for at least 4 weeks prior to the biopsy visit.
    4. 2010 ACR / EULAR Rheumatoid Arthritis classification criteria for a diagnosis of Rheumatoid Arthritis.
    5. Over 18 years of age
    6. Patient must be capable of giving informed consent
    7. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures

    *Reference to NICE guidelines: 1.1 Rituximuab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or intolerance of other disease-modifying anti-rheumatic drugs (DMARDS), including treatment with at least one tumour necrosis factor alpha (TNF alpha) inhibitor therapy.
    1. Que hayan fracasado a tratamientos anti-TNF (respondedores inadecuados ?RI). Esto incluye pacientes que han fracasado por toxicidad.
    2. Que sean elegibles para recibir tratamiento con Rituximab según las recomendaciones del UK NICE
    3. Que estén recibiendo dosis estándar de Metotrexato durante al menos las 4 semanas antes de la visita de biopsia.
    4. Que cumplan los criterios 2010 ACR / EULAR de clasificación diagnóstica de la de la artritis reumatoide
    5. Mayores de 18 años
    6. Capaces de otorgar el consentimiento informado
    7. Con voluntad y capacidad de cumplir con los procedimienos y visitas del estudio
    E.4Principal exclusion criteria
    1.Women who are pregnant or breast-feeding
    2.Women of child-bearing potential, or males whose partners are women of child-bearing potential, unwilling to use effective contraception during the study and for at least 6 months after stopping study treatment.
    3.History of or current primary inflammatory joint disease or primary autoimmune disease other than RA
    4. Prior exposure to Rituximab or Tocilizumab for the treatment of RA
    5.Treatment with any investigational agent ? 4 weeks prior to baseline or < 5 half lives of the investigational drug
    6.Intra articular or parenteral corticosteroids ? 4 weeks prior to biopsy visit (Visit 2)
    7. Oral Prednisolone more than 10mg per day or equivalent ? 4 weeks prior to biopsy visit (Visit 2)
    8.Active infection
    9.Septic arthritis within a native joint within the last 12 months
    10.Sepsis of a prosthetic joint within 12 months or indefinitely if the joint remains in situ
    11.Known HIV or hepatitis B/C infection. Hepatitis B screening test must be performed at or in the preceding 3 months of screening visit.
    12.Latent TB infection unless they have completed adequate antibiotic prophylaxis
    13.Malignancy (other than basal cell carcinoma) within the last 10 years
    14.New York Heart Association (NYHA) grade 3 or 4 congestive cardiac failure
    15.Demyelinating disease
    16.Latex allergy or allergy to any excipients of Rituximab or Tocilizumab
    17.Any other contra-indication to the study medications as detailed in their summaries of product characteristics (SmPC) including low IgG levels at clinician's discretion
    18.Receipt of live vaccine <4 weeks prior to first infusion
    19. Major surgery in 3 months prior to first infusion
    20.Presence of a transplanted organ (with the exception of a corneal transplant >3 months prior to screening)
    21.Known recent substance abuse (drug or alcohol)
    22.Poor tolerability of venepuncture or lack of adequate venous access for required blood sampling during the study period.
    23.Patients unable to tolerate synovial biopsy or in whom this is contraindicated (e.g. patients on anti-coagulants).
    24. Patients currently recruited to other clinical trial(s) involving an investigational medicinal product (except any observational follow-up periods not involving an IMP).
    25. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgement of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgement of the investigator, would make the patient inappropriate for entry into this study
    1. Mujeres embarazadas o lactantes
    2. Mujeres en edad fértil
    3. Historia de enfermedades autoinmunes o inflamatorias diferentes de la AR.
    4. Tratamiento previo con Rituximab o Tocilizumab para la AR
    5. Tratamiento con medicamentos en investigación en las 4 semanas previas o 5 semividas del fármaco previas a la visita basal.
    6. Uso de corticoides intraarticulares o parenterales en las 4 semanas previas a la biopsia
    7. Uso de más de 10 mg/día de prednisolona oral o equivalente en las 4 semanas previas a la biopsia
    8. Infección activa.
    9. Artritis séptica en los últimos 12 meses..
    10. Infección crónica por VIH, VHB o VHC
    11. Tuberculosis latente excepto si se ha finalizado la profilaxis.
    12. Cáncer en los últimos 10 años (con excepción de carcinoma basocelular)
    13. Insuficiencia cardiaca grado 3 o 4 de la NYHA
    14. Enfermedad desmielinizante.
    15. Alergia al látex o a los excipientes de Rituximab o Tocilizumab
    16. Haber recibido vacunas vivas en las últimas 4 semanas antes de la infusión
    17. Pacientes en los que la biopsia está contraindicada (p.ej: en tratamiento anticoagulante) o no se tolera

    18.Haber recibido alguna vacuna viva 4 semanas antes de la primera infusión
    19. cirugía 3 meses antes de la primera infusión
    20. la presencia de un órgano trasplantado (con la excepción de un trasplante de córnea 3 meses antes de la proyección)
    21. reciente abuso de sustancias (alcohol o drogas)
    22. pobre tolerabilidad de venopunción o la falta de un acceso venoso adecuado para tomar muestras de sangre necesarias durante el período de estudio.
    23. pacientes incapaces de tolerar la biopsia sinovial o que presenten alguna contraindicación (por ejemplo, los pacientes con tratamiento anticoagulante).
    24. los pacientes formana parte de otro ensayo clínico u otra prueba clínica que involucre a un medicamento en investigación (excepto estudios obserbacionales que no impliquen a un IMPD).
    25. otra condición médica o psiquiátrica aguda o crónica severa, o anormalidad de los análisis de laboratorio, exceso de riesgo asociado a la participación en el estudio o de la administración del fármaco o que, a juicio del investigador sea inadecuada la entrada del paciente en el presente estudio
    E.5 End points
    E.5.1Primary end point(s)
    The main aim of this project is to test the hypothesis that the presence or absence of specific synovial cellular and molecular signatures (B cells and B cell-associated signatures), assessed following a synovial tissue biopsy, will enrich for response/non-response to the B cell depleting anti-CD20 monoclonal antibody (mAb) Rituximab.

    Therefore, while this study can be thought of as three distinct clinical trials in separate synovial histomorphological phenotypes (1. B cell rich, 2. B cell poor and 3. Germinal centres)with each sub group randomised to Rituximab or Tocilizumab; the Primary outcome measure is the proportion of patients achieving a CDAI (Clinical disease activity index) response at 16 weeks from baseline.

    The primary analysis will focus on whether there is a superiority of Tocilizumab over Rituximab in histologically defined ?B cell poor patients?.
    El objetivo principal de este proyecto es probar la hipótesis de que la presencia o ausencia de cel específicas sinoviales y moleculares (linfocitos B y asociada a la célula de B), evaluados después de una biopsia del tejido sinovial, mejorarán la respuesta/no respuesta de la célula de B- ligadas al anticuerpo monoclonal anti-CD20 Rituximab (mAb).

    Por lo tanto, mientras que este estudio puede ser pensado como tres distintos ensayos clínicos en fenotipos histomorfológicos sinovial separados (1. Ricos en células b, 2. Célula de b pobre y 3. Centros germinales) con cada subgrupo al azar a Rituximab o Tocilizumab; la medida de resultado primaria es la proporción de pacientes que lograron una respuesta (índice de actividad de la enfermedad clínica) CDAI en 16 semanas desde el inicio.

    El análisis primario se centrarán en si hay una superioridad de Tocilizumab sobre Rituximab en la histológia definiendo 'los pacientes pobres encélulas B'.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The timepoint for evaluation of the primary end point will be at 16 weeks from baseline.
    evaluación de end point primario: será a las 16 semanas de la visita basal
    E.5.2Secondary end point(s)
    In addition we will also examine:
    1. For the B-cell rich synovial pathotypes, we aim to show non-inferiority of Rituxumab compared to Tocilizumab.
    2. Germinal Centre pathotypes will constitute an exploratory component to the trial as insufficient power will be generated to show a significant difference in clinical response between each treatment.
    3. Area under the curve (AUC) of mean improvement in DAS28 over time between 0, 16 and 48 weeks.
    4. Percentage of patients with low disease activity (DAS28 < 3.2) at 12, 24, 36, 48, 96 weeks
    5. Percentage of patients in remission (DAS28 < 2.6) at 16 and 48 weeks
    6. Percentage of patients with ACR 20, 50 and 70 response rates at 16, 48 and 96 weeks
    7. Percentage of patients with a low clinical disease activity index score (CDAI)
    8. Mean % change in DAS28 between baseline and 16, 48 and 96 weeks
    9. Mean % change in clinical disease activity index score (CDAI) between baseline and 16, 48 and 96 weeks
    10. Mean change in HAQ score between baseline and 16, 48 and 96 weeks
    11. Change in Fatigue score between baseline and 16, 48 and 96 weeks
    12. Serious adverse events over 12 months; the rate of serious adverse events in the 16 week period following a switch from one technology to the other will be compared
    13. Mean change in erosive score by the van der Heijde/Sharp scoring system at 24 and 48 weeks.
    14. Reduction in US 2D grey scale and power Doppler signal at 16, 48 and 96 weeks.
    15. The effect of synovial immuno-histology on drug response rates
    Además también examinaremos:
    1. para la b-célula patotipos sinovial ricos, nuestro objetivo es demostrar la no inferioridad de Rituxumab comparado con Tocilizumab.
    2.el centro germinal de patotipos constituirá un componente exploratorio para mostrar una diferencia significativa en la respuesta clínica entre cada tratamiento.
    3. el área bajo la curva (AUC) de mejoría media en DAS28 con el tiempo entre 0, 16 y 48 semanas.
    4. porcentaje de pacientes con enfermedad baja actividad (DAS28 3.2) en 12, 24, 36, 48, 96 semanas
    5. porcentaje de pacientes en remisión (DAS28 2.6) en 16 y 48 semanas
    6. porcentaje de pacientes con ACR 20, 50 y 70 las tasas de respuesta en el 16, 48 y 96 semanas
    7. porcentaje de pacientes con un índice de actividad de la enfermedad clínica baja puntuación (CDAI)
    8. cambio en DAS28 entre la línea de fondo y 16, 48 y 96 semanas
    9. cambio en el índice de actividad de la enfermedad clínica puntuación (CDAI) entre la línea de fondo y 16, 48 y 96 semanas
    10. cambio en puntuación HAQ basal y 16, 48 y 96 semanas
    11. cambio en la puntuación de fatiga entre la línea de fondo y 16, 48 y 96 semanas
    12. efecto adverso graves durante 12 meses; se comparará la tasa de eventos adversos graves en el período de 16 semanas
    13. cambio en la puntuación erosivo por la HeijdeSharp van der sistema de puntuación a las 24 y 48 semanas.
    14. reducción en escala de grey 2D de Estados Unidos y la señal del Doppler en 16, 48 y 96 semanas.
    15. el efecto de inmuno-histología sinovial en las tasas de respuesta de drogas
    E.5.2.1Timepoint(s) of evaluation of this end point
    The timepoints for evaluation of secondary end points will be up to 96 weeks from baseline.
    Los endpoint secundarios serán en la semana 96 del estudio
    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 No
    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 Yes
    E.8.1.1Randomised Yes
    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) 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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 No
    E.8.7Trial has a data monitoring committee Yes
    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
    This will be the last visit of the last patient after 24 months of follow up.
    está prevista la última visita del último paciente después de 24 meses de seguimiento .
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days30
    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: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 180
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 180
    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)
    Both therapies have NICE approval and licensed within the UK for use within this patient population. Therefore patients treatment will continue to be funded by local Primary Care Trusts following cessation of the clinical study.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-07-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-10
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