Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   35554   clinical trials with a EudraCT protocol, of which   5841   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2014-004996-22
    Sponsor's Protocol Code Number:7962-CL-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:2016-02-03
    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 number2014-004996-22
    A.3Full title of the trial
    A Phase 2a, Randomized, Double-blind, Placebo- and Naproxen-controlled, Parallel-group Study to Assess the Analgesic Efficacy of ASP7962 in Patients with Pain Due to Osteoarthritis of the Knee
    Estudio Fase IIa, aleatorizado, doble-ciego, paralelo, controlado con placebo y Naproxeno para evaluar la eficacia analgésica de ASP7962 en pacientes con dolor secundario a osteoartritis en rodilla
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial to investigate the efficacy of ASP7692 in patients with pain due to arthritis in the knee
    Estudio para investigar la efficacia del ASP7692 en pacientes con dolor debido a osteoartritis en la rodilla
    A.3.2Name or abbreviated title of the trial where available
    OAK Study
    Estudio OAK
    A.4.1Sponsor's protocol code number7962-CL-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 SponsorAstellas Pharma Europe B.V.
    B.1.3.4CountryNetherlands
    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 supportAstellas Pharma Europe B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationChiltern International Spain S.A
    B.5.2Functional name of contact pointRicardo Diaz
    B.5.3 Address:
    B.5.3.1Street AddressCentro Empresarial Euronova 3, Ronda de Poniente 10, Planta 2
    B.5.3.2Town/ cityTres Cantos, Madrid
    B.5.3.3Post code28760
    B.5.3.4CountrySpain
    B.5.4Telephone number3491187 27 00.
    B.5.5Fax number3491187 28 49.
    B.5.6E-mailspain.regulatory@chiltern.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 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.3.2Product code ASP7962
    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 INNASP7962
    D.3.9.3Other descriptive nameASP7962
    D.3.9.4EV Substance CodeSUB124281
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.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 NAPROXEN Tablets USP
    D.2.1.1.2Name of the Marketing Authorisation holderTeva Pharmaceuticals USA Inc
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 Capsule
    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 INNNAPROXEN
    D.3.9.3Other descriptive nameNAPROXEN
    D.3.9.4EV Substance CodeSUB09159MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Osteoarthritis of the knee
    Osteoartritis de la rodilla
    E.1.1.1Medical condition in easily understood language
    Osteoarthritis of the knee
    Osteoartritis de la rodilla
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10031165
    E.1.2Term Osteoarthritis knee
    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
    Evaluate the analgesic efficacy of ASP7962 relative to placebo
    Evaluar la eficacia analgésica de ASP7962 en comparación con placebo
    E.2.2Secondary objectives of the trial
    Secondary
    Evaluate the efficacy of ASP7962 relative to placebo on pain on walking, function and stiffness Evaluate the time course of efficacy of ASP7962 relative to placebo
    Evaluate the improvement in overall patient status of ASP7962 relative to placebo
    Evaluate the safety and tolerability of ASP7962 relative to placebo
    Evaluar la eficacia de ASP7962 en comparación con placebo en cuanto al dolor al andar, a la funcionalidad y a la rigidez
    Evaluar el curso temporal de la eficacia de ASP7962 en comparación con placebo
    Evaluar la mejoría en el estado general del paciente de ASP7962 en comparación con placebo
    Evaluar la seguridad y la tolerabilidad de ASP7962 en comparación con placebo
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations.
    2. Patient is a male or female patient and aged 18 to 75 years, at screening.
    3. Patient has a primary diagnosis of OA of the index knee with symptoms for at least 6 months prior to screening and patient meets American College of Rheumatology clinical classification criteria for OA of the knee, defined by the following.
    Knee pain and at least 3 of the following 6 (a-f):
    a) Age > 50 years
    b) Morning stiffness < 30 minutes
    c) Crepitus on active motion
    d) Bony tenderness
    e) Bony enlargement
    f) No palpable warmth of synovium
    4. Patient has a radiographic image of the index knee (according to the minimum quality criteria for radiographic image as set by the central radiology reader) showing evidence of OA with a Kellgren-Lawrence grade 2 or 3 at screening.
    5. Patient has moderate to severe index knee pain (pain due to OA of the knee at least 5 days per week for the last 3 months prior to screening, as determined by patient?s medical history).
    6. Patient is ambulatory and the index knee must not contain any orthopedic and/or prosthetic device.
    7. WOMAC pain subscale score (with a 48-hour recall period) in the index knee ? 4 at baseline (visit 2 predose, mean of all questions on pain subscale).
    8. Mean daily index knee average pain score between ? 4 and ? 9 (0-10 NRS), from the available recordings in the last 4 days prior to visit 2.
    9. WOMAC physical function subscale score ? 4 at baseline (visit 2 predose, mean of all questions on the physical function subscale with a 48-hour recall period).
    10. Patient is willing to discontinue all current pain medications during the baseline and treatment periods (until day 57) (except for allowed rescue medications). Low dose aspirin for cardioprophylaxis is allowed.
    11. Patient is compliant with daily pain recording.
    12.Male patient and their female spouse/partners who are of childbearing potential must be using a barrier method* and 1 form of highly effective birth control** starting at screening and continuing throughout the study period and for 90 days after the final study drug administration.
    13. Male patient must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.
    14. Female patient must either:
    Be of non childbearing potential:
    post-menopausal (defined as at least 1 year without any menses) prior to screening, or
    documented surgically sterile
    Or, if of childbearing potential:
    agree not to try to become pregnant during the study and for 28 days after the final study drug administration,
    and have a negative pregnancy test at screening and at baseline (visit 2 predose),
    and if heterosexually active, agree to consistently use a barrier method* and 1 form of highly effective birth control** starting at screening and continuing throughout the study period and for 28 days after the final study drug administration15. Female patient must agree not to breastfeed starting at screening and continuing throughout the study period and for 28 days after the final study drug administration.
    16. Female patient must not donate ova starting at screening and continuing throughout the study period and for 28 days after the final study drug administration.
    17. Patient agrees not to participate in another investigational study from screening through the follow-up period (until day 57).
    * Barrier methods of birth control include:
    ?Condom or occlusive cap (diaphragm or cervical/ vault caps) with spermicidal foam/gel/film/cream/suppository
    ** Highly effective forms of birth control include:
    ?Consistent and correct usage of established oral contraception (including progestogen-only oral contraception associated with inhibition of ovulation).
    ?Established intrauterine device (IUD) or intrauterine system (IUS).
    Waivers to the inclusion criteria will NOT be allowed.
    1. Debe obtenerse del paciente el consentimiento informado por escrito aprobado por el Comité independiente de ética (CIE) o el Consejo institucional de revisión (CIR) y la comunicación de privacidad según estipule la normativa nacional antes de que se realice ningún procedimiento relacionado con el estudio (incluida, si es pertinente, la retirada del tratamiento prohibido).
    2. El paciente es un varón o una mujer y tiene entre 18 y 75 años en la selección.
    3. El paciente tiene un diagnóstico principal de artrosis en la rodilla de referencia con síntomas que duran como mínimo 6 meses antes de la selección y el paciente cumple los criterios de clasificación clínica de artrosis de rodilla del American College of Rheumatology, definidos por lo siguiente:
    Dolor de rodilla y por lo menos 3 de los 6 puntos siguientes (a-f):
    a) Edad >50 años
    b) Rigidez matutina < 30 minutos
    c) Crepitación con el movimiento activo
    d) Dolorimiento óseo
    e) Aumento de tamaño óseo
    f) Ausencia de calor palpable de la membrana sinovial
    4. El paciente tiene una imagen radiográfica de la rodilla de referencia (de acuerdo con los mínimos criterios de calidad de una imagen radiográfica establecidos por el lector radiológico central) que muestra evidencia de artrosis con un grado de Kellgren-Lawrence de 2 o 3 en la selección (según la lectura central).
    5. El paciente tiene dolor de moderado a intenso en la rodilla de referencia (dolor secundario a la artrosis de la rodilla un mínimo de cinco días a la semana durante los tres últimos meses anteriores a la selección, determinado en función de la historia clínica del paciente).
    6. El paciente no está encamado y la rodilla de referencia no debe contener ningún dispositivo ortopédico ni protésico.
    7. Puntuación de la subescala del dolor del WOMAC (con un periodo de recuerdo de 48 horas) en la rodilla de referencia ? 4 en la visita basal (Visita 2 antes de la dosis, media de todas las preguntas de la subescala del dolor).
    8. Puntuación media diaria del dolor promedio de la rodilla de referencia entre ? 4 y ? 9 (0-10 NRS), de los registros disponibles en los 4 últimos días anteriores a la visita 2.
    9. Puntuación de la subescala de la función física del WOMAC ? 4 en la visita basal (visita 2 antes de la dosis, media de todas las preguntas de la subescala de la función física con un periodo de recuerdo de 48 horas).
    10. El paciente está dispuesto a dejar de tomar todos los analgésicos actuales durante los periodos basal y de tratamiento (hasta el día 57) (excepto para los tratamientos de rescate permitidos). Se permite una dosis baja de aspirina como cardioprofilaxis.
    11.Paciente cumple el registro diario del dolor. Se definirá cumplimiento con respecto a la cumplimentación del diario si se anotan valoraciones promedio diarias del dolor al menos 5 días en el periodo basal, de los cuales como mínimo 3 días correspondan a los últimos 4 días anteriores a la visita 2.
    13. El paciente varón no debe donar esperma empezando en la selección y continuando durante todo el periodo del estudio y durante 90 días después de la administración final del fármaco experimental.
    14. Una paciente debe:
    ? O bien no ser fértil:
    ? Posmenopáusica (como mínimo 1 año sin menstruaciones) antes de la selección, o bien
    ? haber sido esterilizada quirúrgicamente, y documentado
    ? O, si es fértil:
    ? aceptar no intentar quedarse embarazada durante el estudio y durante 28 días después de la administración final del fármaco experimental,
    ? Tener una prueba de embarazo negativa en la selección y en la visita basal (visita 2 antes de la dosis), y
    ? si es heterosexualmente activa, aceptar utilizar constantemente 2 formas de control de la natalidad muy eficaces* (como mínimo una de las cuales debe ser un método de barrera) empezando en la selección y continuando durante todo el periodo del estudio y durante 28 días después de la administración final del fármaco experimental.
    15. La paciente debe aceptar no dar el pecho empezando en la selección y continuando durante todo el periodo del estudio y durante 28 días después de la administración final del fármaco experimental.
    16. La paciente no debe donar óvulos empezando en la selección y continuando durante todo el periodo del estudio y durante 28 días después de la administración final del fármaco experimental.
    17. El paciente acepta no participar en otro estudio en fase experimental desde la selección hasta acabar el periodo de seguimiento (hasta el día 57).
    E.4Principal exclusion criteria
    1.CH of suicide attempt/ suicidal behavior. Suicidal ideation within last 12m or significant risk to commit suicide, judged by inv. at Scr & rando 2.Current or prior psychosis, major depressive disorder or other CS psychiatric disorder 3. Current or prior CS neurologic disease: peripheral neuropathy, stroke, cognitive impairment and seizure 4.CS musculoskeletal disorder (exception OA), CV,GI, endocrinologic (DM allowed if controlled HbA1c? 7.1% and no peripheral neuropathy), hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, dermatologic, renal &/or other major disease judged by inv. 5.Active malignancy or CH of malignancy (except treated nonmelanoma skin cancer) within past 5y. 6.CH of inflammatory arthritis: rheumatoid arthritis or CH of RPOA, osteonecrosis or avascular necrosis of bone &/or joints or other Dx that may increase risk of RPOA 7.Findings suggestive of RPOA/increased risk for RPOA on Scr X-ray of index or non-index joints (central reading) 8.CH of shoulder Sx ,CS trauma or current symptoms: pain or impaired range of motion at shoulder joint 9.Coagulopathy, anticoagulant tt or diagnosed thrombocytopenia or functional platelet disorder 10.CH of paracetamol intolerance or existence of medical condition or use of concomitant medication (CM) being paracetamol contraindicated 11.Naproxen(Nx) contraindication: hypersensitivity to Nx or Nx sodium; asthma, rhinitis, nasal polyps, urticarial or allergic-type reactions after taking aspirin or other NSAIDs; anticipated CABG during study; active or CH of peptic ulceration; active or CH of GI bleeding (exception hemorrhoids) or perforation 12.Tramadol (TD) contraindication: TD hypersensitivity; monoamine oxidase inhibitor used within 2w prior to Scr or during Scr or BSL periods 13.BMI>39 kg/m2. 14.CS abnormality on 12-lead ECG at Scr or BSL (v2 predose) 15.CH of acute coronary syndrome, ischemic or hemorrhagic stroke, transient ischemic attack, coronary or peripheral revascularization procedure, HF, ischemic heart disease, unexplained syncope, cardiac arrest, CS cardiac arrhythmias, heart block (first degree heart block allowed if PR<210msec), torsade de pointes, structural heart disease or personal/family CH of long QT syndrome 16.Resting FR<50or>100bpm; SBP>160mmHg;DBP>90 mmHg at Scr or BSL(v2 predose). If repeat measurement meets above criteria, pt to be excluded 17.CH of unexplained syncopal events or symptomatic orthostatic hypotension at Scr or BSL (v2 predose) 18.According to inv. CS abnormalities in clinical chemistry, hematology or urinalysis at Scr 19.AST, ALT,TBL>1.5 times ULN at Scr 20.GFR?60mL/min/1.73m2(MDRD calculation) at Scr 21.Positive result for HBSLAg, anti-HBc, anti-HAV [IgM], anti-HCV or HIV 1 antibodies &/or HIV 2 at Scr 22.Any IP within 28 d (or 5 half-lives of IP, whichever longer) before Scr or scheduled to receive IP other than blinded study tt during the course of study 23. Pt previously received NGF antibodies 24.Major Sx/orthopedic Sx within 3m before Scr or plans for surgical intervention during study 25.Not suitable candidate for joint replacement & unable to stop chronic NSAID use 26.Intra-articular corticosteroidwithin3m prior to Scr, intraarticular hyaluronic acid within6m prior to Scr or intra-articular local anesthetic within 12m prior to Scr or any of these therapies during Scr or BSL periods 27.Systemic corticosteroids within 30d before Scr or during Scr or BSL periods 28. Any med. or nonmed therapy effective reducing pain of OA of the knee:OTC products (exception ice packs, rest &paracetamol) during BSL period 29.Pt started or stopped physiotherapy, acupuncture or transcutaneous electrical nerve stimulation related to tt of the index knee within 4w prior to Scr or during the Scr or BSL periods.Stable regimens of introduced >4w prior to Scr will be allowed if regimen continues unchanged during study 30.Used opioids >4 days during week preceding Scr/Scr period; or received any opioids during BSL period 31.Used DPP4 inhibitors within 12m prior to v2 32.Systemic inducer of CYP450 3A metabolism in 3m before v2. 33.No complied with requirements for restricted and prohibited medications and nonmed therapies during BSL period 34.Positive drug Screen for alcohol or recreational drugs or nonprescribed controlled substances at Scr or BSL 35.CH of alcohol or drug abuse/dependence/misuse within 1y prior to Scr 36.Painful condition syndrome/other concurrent medical/arthritic condition with potential to confound assessment of pain in index knee 37. HADS score>12 on either subscale at Scr or BSL (v2 predose) 38.Pt involved in ongoing or settled workers compensation claim, disability or litigation related to index knee or pain problem 39.Condition (inv. opinion) makes pt unsuitable for study participation 40. Employee of Astellas Group, CRO involved or inv. site executing the study.
    1Ant suicidio/comp/ideas suicidas en últimos 12m a juicio del inv en v.sel. y aleatorización.2Psicosis/TDM/otros trastornos Psiquiátricos.3Enf.Neurológica:neuropatía periférica, ACV, deterioro cognitivo y convulsiones.4Trast. musculoesquelético (excep. de OA), cardiovascular, gastrointestinal, endocrinológico (DM permitida si controlada:HbA1c ? 7,1 % sin neuropatía periférica),hematológico,hepático, inmunológico, metabólico,urológico, pulmonar, dermatológico, renal u enf mayor a juicio del inv.5Neoplasia maligna activa o ant de neoplasia maligna (excep. cáncer cutáneo no melanoma tratado) en los 5a ant.6Ant artritis inflamatoria:AR o OAPR, osteonecrosis o necrosis vascular del hueso/articulaciones u otros q pueden aumentar riesgo de OAPR.7Rx en v.sel de las articulaciones de ref o no ref sugestivas de OA de progresión rápida(según lab.central).8Ant.Cx de hombro, traumatismo o síntomas actuales:dolor o deterioro amplitud del mov en articulación del hombro.9Coagulopatía, tto con ACO o con trombocitopenia o trast. funcional plaquetario.10Ant. intolerancia a paracetamol o enf.o tto concomitante para los q. esté contraindicado paracetamol.11Contraindic. naproxeno(Nx),hipersensibilidad conocida a Nx o a Nx sódico;asma, rinitis,pólipos nasales,reacciones urticariales o alérgicas tras aspirina o AINE,previsión de Cx de revasculariazación aortocoronaria durante el estudio,ant.de úlcera péptica, o úlcera péptica activa, Hemorragia (excep. hemorroides) o perforación.12Contraindicación tramadol (TD):hipersensibilidad conocida a TD. Pac ha tomado IMAO en las 2s ant. a v.sel. o durante periodo v.sel o basal.13IMC>39 kg/m2.14.Anomalía ECG 12 derivac. en v.sel. o basal (V2 predosis).15Ant SCA, ACV isquémico/hemorrágico, AIT, procedimiento de revascularización coronaria o periférica, IC, cardiopatía isquémica, síncope idiopático, parada cardíaca, arritmias cardiacas, bloqueo de rama (bloqueo de 1er grado permitido si intervalo PR?210ms), torsade de pointes, cardiopatía estructural o ant. personales/familiares SQT prolongado.16FC en reposo<50ó>100lpm;TAS>160mmHg,TAD>90 mmHg en v.sel. o v.basal (V2predosis)Si la medida repetida cumple crit.anteriores, el pac será excluido.17Ant.de síncope idiopático o hipotensión ortostática sintomática en v.de sel. o en v.basal (V2 predosis).18Valores anormales en BQ, hematología o análisis de orina en v.sel.19Perfil hepático ALT,AST,BLT>1,5 veces LSN en sel.20TFG ? 60 ml/min /1,73 m2,MDRD en selecc.21 Análisis + HBsAg, anti-HBc, AcHepA,Ig M anti-VHA, IgM anti-VHC o AcVIHI/VIHII en sel.22Pac en tto en fase experimental en 28d(o 5semividas del fármaco,lo que sea más largo) antes de sel o está programado para recibir tto experimental distinto de los ttos enmascarados del estudio.23Ha recibido con anterioridad AcFCN.24Pac sometido a Cx mayor o Cx ortopédica en 3m ant a sel o prevista una Cx durante estudio.25Pac no adecuado para artroplastia y no puede dejar de tomar AINE crónicos.26Ha recibido corticosteroides intraarticulares en los 3ms ant a la sel, Ac. hialurónico intraarticular en los 6m ant a la sel o anestesia local intraarticular en 12m ant a la sel o cualquiera de estos ttos durante los periodos de sel o basal.27Ha recibido corticosteroides sistémicos en los 30d antes de la sel. o drante los periodos de sel. o basal (corticosteroides vía tópica, nasal o inhalación permitidos).28Ha recibido ttos o terapias no medicamentosas con eficacia en reducción dolor de OAR:OTC, (salvo compresas de hielo, reposo y paracetamol) durante el periodo basal.29Ha iniciado/interrumpido fisioterapia,acupuntura o estimulación nerviosa eléctrica transcutánea relacionada con tto rodilla de ref en las 4sem ant a la sel o durante periodos de sel o basal.Se permitirán pautas estables de ttos introducidos >4sem antes de la sel si la mantiene invariable durante el estudio.30Opioides durante>4 d en la sem precedente a la sel./durante periodo de sel./ha recibido cualquier opioide en el periodo basal.31DPP-4 en 12m ant a la V2.32Uso de inductores sistémico de CIP 450 3A en los 3m ant a V2.33No cumple requisitos relativos a ttos restringidos y prohibidos y ttos no medicamentosos en el periodo basal.34Cribado + en alcohol/drogas/sustancias controladas no recetadas en periodo de sel/basal.35Ant. de toxicomanía/dependencia/abuso de alcohol/drogas en año ant a v.sel.36Pac con Sdr. Doloroso/otras enf.médicas/artríticas concurrentes que pueden confundir la evaluacion de dolor en rodilla de ref.37Puntuación HADS>12 en cualquier subescala en periodo de sel o basal (V2 predosis).38Pac implicado en solicitud de indemnización por acc.laboral, incapacidad o litigio en curso o resuelto relacionado con rodilla de ref. o cualquier problema doloroso.39Otra enf. q hace q no sea adecuado para participar en el estudio.40Pac. empleado del G.Astellas, de la CRO participante o del centro donde se lleve a cabo el estudio
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is change from baseline to week 4 in WOMAC pain subscale score.
    Cambio en la puntuación de la subescala de dolor del WOMAC desde la visita basal hasta la semana 4
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 4
    Semana 4
    E.5.2Secondary end point(s)
    Analysis of Secondary Endpoints
    The secondary efficacy endpoints are defined in [Section 2.3.2]
    Treatment Period
    The change from baseline to EOT in WOMAC pain subscale score will be analyzed using an
    Analysis of Covariance (ANCOVA) with treatment group and study site as fixed effects and
    baseline value as a covariate. The EOT refers to the last assessment during the treatment
    period. The ANCOVA will present LS mean, SE and 2-sided 90% CI for mean changes from
    baseline within each treatment group (placebo, ASP7962, and naproxen). Difference in
    LS means between ASP7962 and placebo with corresponding 2-sided 90% CI and the
    Sponsor: APEB ISN/Protocol 7962-CL-0022
    EudraCT number 2014-004996-22
    - CONFIDENTIAL -
    06 Nov 2015 Astellas Page 78 of 110
    Version 2.0 Incorporating Substantial Amendment 1
    difference in LS means between naproxen and placebo with corresponding 2-sided 80% CI
    will be derived. The differences in the LS mean estimates will be used to obtain 1 -sided
    P values for ASP7962 versus placebo and naproxen versus placebo.
    The change from baseline to EOT for WOMAC physical function and stiffness subscale
    scores, WOMAC total score, WOMAC walking pain, mean daily average pain NRS score,
    and PGA will be analyzed using the same ANCOVA model as described above for the
    change from baseline to EOT in WOMAC pain subscale score.
    The MMRM analysis as described in [Section 7.4.1.1] for the primary efficacy analysis will
    be used to analyze the following secondary efficacy endpoints during the treatment period:
    ? Change from baseline to weeks 1 and 2 for WOMAC pain subscale score (WOMAC
    pain subscale scores from the MMRM model with weeks 1, 2 and 4 included)
    ? Change from baseline to weeks 1, 2 and 4 for WOMAC physical function and stiffness
    subscale scores, WOMAC total score, and WOMAC walking pain
    ? Change from baseline to weeks 1, 2, 3 and 4 for mean daily average pain score based on
    the NRS
    ? Change from baseline to weeks 1, 2 and 4 for PGA
    The proportion of patients who have a ? 30% reduction and ? 50% reduction from baseline to
    EOT in WOMAC pain subscale score will be summarized for each treatment group, as well
    as the difference in proportion between ASP7962 and placebo and between naproxen and
    placebo. The difference in proportion between ASP7962 and placebo and between naproxen
    and placebo will be analyzed using a 1 -sided Fisher?s exact test.
    7.4.2 Análisis de los criterios de valoración secundarios
    Los criterios prendarios de las variables secundarias de eficacia se definen en la [Sección 2.3.2].
    Periodo de tratamiento
    El cambio en la puntuación de la subescala de dolor del WOMAC desde el valor basal hasta el FdT se analizará utilizando un análisis de la covarianza (ANCOVA) con el grupo de tratamiento y el centro del estudio como efectos fijos y el valor basal como una covariable. FdT se refiere a la última evaluación durante el periodo de tratamiento. El ANCOVA presentará la media de los MC, el EE y el IC bilateral del 90% para los cambios medios con respecto al valor basal dentro de cada grupo de tratamiento (placebo, ASP7962 y naproxeno). Se obtendrá la diferencia de las medias de los MC entre ASP7962 y placebo con el correspondiente intervalo de confianza bilateral del 90% y la diferencia en las medias de los MC entre naproxeno y placebo con el correspondiente intervalo de confianza bilateral del 80%. Las diferencias en las estimaciones de las medias de los MC se utilizarán para obtener valores de P unilaterales para ASP7962 en comparación con placebo y naproxeno en comparación con placebo.
    El cambio desde el valor basal hasta FdT para las puntuaciones de la subescala de función física y de rigidez del WOMAC, la puntuación total del WOMAC, el dolor al caminar del WOMAC, la puntuación NRS media del dolor promedio diario y la EGP se analizará utilizando el mismo modelo ANCOVA que se acaba de describir para el cambio en la puntuación de la subescala de dolor del WOMAC entre el valor basal y el FdT.
    El análisis del MMRM como se describe en [Sección 7.4.1.1] para el análisis principal de eficacia se utilizará para analizar los siguientes criterios secundarios de valoración de la eficacia durante el periodo de tratamiento:
    ? Cambio en la puntuación de la subescala de dolor del WOMAC desde la visita basal hasta las semanas 1 y 2 (puntuaciones de la subescala de dolor del WOMAC del modelo MMRM con las semanas 1, 2 y 4 incluidas)
    ? Cambio en las puntuaciones de la subescala de la función física y la rigidez del WOMAC, la puntuación total del WOMAC y el dolor al caminar del WOMAC entre la visita basal y las semanas 1, 2 y 4
    ? Cambio en la puntuación media del dolor promedio diario evaluada según la NRS desde la visita basal hasta las semanas 1, 2, 3 y 4
    ? Cambio desde la visita basal hasta las semanas 1, 2 y 4 para la EGP

    Para cada grupo de tratamiento se resumirá la proporción de pacientes que tengan una reducción ? 30% y una reducción ? 50% desde el valor basal hasta FdT en la puntuación de la subescala de dolor del WOMAC, así como la diferencia en la proporción entre ASP7962 y placebo y entre naproxeno y placebo. La diferencia en la proporción entre ASP7962 y placebo y entre naproxeno y placebo se analizará utilizando una prueba exacta unilateral de Fischer.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 1, week 2, week 3, week 4
    Semana 1, semana 2, semana 3, semana 4
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    LVLS
    Ultima visita del último paciente
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    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 state165
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 205
    F.4.2.2In the whole clinical trial 205
    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)
    None
    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 Decision2016-03-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-09-29
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2019 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA