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    Summary
    EudraCT Number:2016-005020-29
    Sponsor's Protocol Code Number:R475-OA-1611
    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:2017-12-01
    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 number2016-005020-29
    A.3Full title of the trial
    A Phase 3 Randomized, Double-blind, Multi-dose, Placebo and Naproxen-Controlled Study to Evaluate the Efficacy and Safety of Fasinumab in Patients with Pain Due to Osteoarthritis of the Knee or Hip
    Estudio en fase III aleatorizado, con doble enmascaramiento, múltiples dosis, controlado con placebo y naproxeno para evaluar la eficacia y la seguridad del fasinumab en pacientes con dolor debido a artrosis de rodilla o cadera
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to determine the safety and the efficacy of fasinumab compared to placebo and naproxen for treatment of adults with pain from osteoarthritis of the knee or hip
    Estudio para determinar la seguridad y eficacia del fasinumab en comparación con las del placebo y naproxeno para el tratamiento de adultos con dolor secundario a la osteoartritis de rodilla o cadera
    A.3.2Name or abbreviated title of the trial where available
    FACT OA1
    FACT OA1
    A.4.1Sponsor's protocol code numberR475-OA-1611
    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 SponsorRegeneron Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportRegeneron Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRegeneron Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address777 Old Saw Mill River Road
    B.5.3.2Town/ cityTarrytown, NY
    B.5.3.3Post code10591
    B.5.3.4CountryUnited States
    B.5.4Telephone number+3491 005 22 32
    B.5.6E-mailsoporte@medinovaresearch.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.3.1Product nameFasinumab
    D.3.2Product code REGN475
    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 INNFasinumab
    D.3.9.1CAS number 1190239-42-9
    D.3.9.2Current sponsor codeREGN475
    D.3.9.3Other descriptive nameFASINUMAB
    D.3.9.4EV Substance CodeSUB128096
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 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 nameFasinumab
    D.3.2Product code REGN475
    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 INNFasinumab
    D.3.9.1CAS number 1190239-42-9
    D.3.9.2Current sponsor codeREGN475
    D.3.9.3Other descriptive nameFASINUMAB
    D.3.9.4EV Substance CodeSUB128096
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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: 3
    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 nameFasinumab
    D.3.2Product code REGN475
    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 INNFasinumab
    D.3.9.1CAS number 1190239-42-9
    D.3.9.2Current sponsor codeREGN475
    D.3.9.3Other descriptive nameFASINUMAB
    D.3.9.4EV Substance CodeSUB128096
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12
    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: 4
    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
    D.2.1.1.2Name of the Marketing Authorisation holderAmneal Pharmaceuticals LLC
    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.3.1Product nameNaproxen
    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.3.9.1CAS number 22204-53-1
    D.3.9.2Current sponsor codeNaproxen
    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 placeboSolution for injection in pre-filled syringe
    D.8.4Route of administration of the placeboSubcutaneous 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
    Pain due to osteoarthritis of the knee or hip
    Dolor debido a la artrosis de rodilla o cadera
    E.1.1.1Medical condition in easily understood language
    Pain of the knee or hip due to a joint disease that results from breakdown of joint cartilage and underlying bone
    Dolor de rodilla o cadera debido a una enfermedad de las articulaciones causada por la destrucción del cartílago articular y hueso subyacente
    E.1.1.2Therapeutic area Body processes [G] - Bones and nerves physological processes [G11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10023476
    E.1.2Term Knee osteoarthritis
    E.1.2System Organ Class 100000004859
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10020108
    E.1.2Term Hips osteoarthritis
    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 primary objective of the study is to evaluate the efficacy of fasinumab compared with placebo, when administered for up to 16 weeks in patients with OA of the knee or hip.
    El objetivo principal del estudio es evaluar la eficacia del fasinumab en comparación con la de un placebo cuando se administran durante un periodo de hasta 16 semanas a pacientes con artrosis de rodilla o cadera.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are:
    1. To evaluate the efficacy of fasinumab compared with naproxen, when administered for up to 16 weeks in patients with pain due to OA of the knee or hip
    2. To evaluate the efficacy of fasinumab compared with placebo, when administered for up to 52 w in patients with pain due to OA of the knee or hip
    3. To assess the safety and tolerability of fasinumab compared with naproxen, when administered for up to 16 weeks in patients with pain due to OA of the knee or hip
    4. To assess the safety and tolerability of fasinumab compared with naproxen, when administered for up to 52 weeks in patients with pain due to OA of the knee or hip
    5. To evaluate the pharmacokinetic (PK) profile of fasinumab administered to patients with pain due to OA of the knee or hip for up to 52 weeks
    6. To evaluate the immunogenicity of fasinumab administered to patients with pain due to OA of the knee or hip for up to 52 weeks
    Objetivos secundarios:
    1. Evaluar la eficacia del fasinumab en comparación con la del naproxeno cuando se administran durante un periodo de hasta 16s a pacientes con dolor por OA de rodilla o cadera
    2. Evaluar la eficacia del fasinumab en comparación con la de un placebo cuando se administran durante un periodo de hasta 52s a pacientes con dolor por OA de rodilla o cadera
    3. Evaluar la seguridad y la tolerabilidad del fasinumab en comparación con las del naproxeno cuando se administran durante un periodo de hasta 16 s a pacientes con dolor por OA de rodilla o cadera
    4. Evaluar la seguridad y la tolerabilidad del fasinumab en comparación con las del naproxeno cuando se administran durante un periodo de hasta 52 s a pacientes con dolor por OA de rodilla o cadera
    5. Evaluar el perfil FC del fasinumab administrado a los pacientes con dolor por OA durante un periodo de hasta 52s
    6. Evaluar la inmunogenicidad del fasinumab administrado a los pacientes "durante un periodo de hasta 52s
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional Pharmacogenomic sub-study
    Subestudio Farmacogenómico Opcional
    E.3Principal inclusion criteria
    A patient must meet the following criteria to be eligible for inclusion in the study:
    1. Male and female patients, at least 18 years of age, at screening
    2. A clinical diagnosis of OA of the knee or hip based on the American College of Rheumatology criteria with radiologic evidence of OA (K-L score ≥2 for the index joint) at the screening visit
    3. Moderate to severe pain in the index joint defined at both the screening and randomization visits
    4. Willing to discontinue current pain medications and to adhere to study requirements for rescue treatments (paracetamol/acetaminophen to be taken as needed with a maximum daily dose of 2500 mg in Europe and 2600 mg in countries outside of Europe)
    5. A history of at least 12 weeks of inadequate pain relief or intolerance to analgesics used for pain due to OA of the knee or hip, as defined by
    a. Inadequate pain relief from acetaminophen/paracetamol AND
    b. Intolerance to or inadequate pain relief from at least 1 opioid or tramadol, unwillingness to take opioid or tramadol therapy for a medically acceptable reason, or lack of access to an opioid or to tramadol
    6. Currently using a stable dose of NSAID, defined as using NSAIDs for approximately 4 days per week over the last 4 weeks.
    7. Willing to discontinue glucosamine sulfate and chondroitin sulfate treatments during the initial 16 weeks of treatment
    8. Stable treatment with glucosamine sulfate and chondroitin sulfate treatments must be stopped during the pre-randomization period
    9. Consent to allow all radiographs and medical/surgical/hospitalization records of care received elsewhere prior to and during the study period to be shared with the investigator
    10. Willing to maintain current activity and exercise levels throughout the study
    11. Willing and able to comply with clinic visits and study-related procedures and willing to provide follow-up information related to any JR surgery that occurs within the period of time covered by their intended participation in the study
    12. Able to understand and complete study-related questionnaires
    Para poder incorporarse al estudio, los pacientes deben cumplir los siguientes criterios:
    1. Hombres y mujeres mayores de 18 años en el momento de la selección
    2. Diagnóstico clínico de OA de rodilla o cadera basado en los criterios del Colegio Estadounidense de Reumatología con signos radiológicos de OA (puntuación ≥ 2 en la escala de K L en la articulación de referencia) durante la visita de selección
    3. Dolor moderado o intenso en la articulación de referencia, determinado tanto durante la visita de selección como durante la de aleatorización
    4. Disposición a suspender el uso actual de analgésicos y de cumplir los requisitos del estudio en lo que se refiere a los tratamientos de rescate (paracetamol a demanda con una dosis diaria máxima de 2500 mg en Europa y 2600 mg en otros países no europeos)
    5. Antecedentes de alivio insuficiente del dolor durante al menos 12 semanas o intolerancia a los analgésicos empleados para el dolor debido a la OA de rodilla o cadera, determinados por:
    a. Alivio insuficiente del dolor por parte del paracetamol, Y
    b. Intolerancia a al menos 1 opioide o al tramadol o alivio insuficiente del dolor por parte de estos, poca disposición a tomar un tratamiento con opioides o tramadol por un motivo médicamente aceptable o falta de acceso a un opioide o al tramadol
    6. Uso actual de una dosis estable de AINE, que se define como el uso de AINE durante aproximadamente 4 días a la semana durante las últimas 4 semanas.
    7. Poca disposición a interrumpir tratamientos con sulfato de glucosamina y sulfato de condroitina durante las primeras 16 semanas de tratamiento
    8. El tratamiento estable con sulfato de glucosamina y sulfato de condroitina debe suspenderse durante el periodo de pre-aleatorización
    9. Consentimiento para permitir que se compartan con el investigador todas las radiografías y registros médicos/quirúrgicos/hospitalarios de la asistencia sanitaria recibida en otros lugares antes y durante el periodo del estudio
    10. Disposición a mantener la cantidad actual de actividad y ejercicio durante todo el estudio
    11. Disposición y capacidad para realizar las visitas al centro y someterse a los procedimientos relacionados con el estudio y disposición a proporcionar información de seguimiento relacionada con cualquier artroplastia que tenga lugar durante la participación prevista del paciente en el estudio
    12. Capacidad para comprender y contestar cuestionarios relacionados con el estudio
    E.4Principal exclusion criteria
    A patient who meets any of the following criteria will be excluded from the study:
    1. Non-compliance with the NRS recording during the pre-randomization period (4 or more consecutive missed diary entries)
    2. History or presence at the screening visit of non-OA inflammatory joint disease (eg, rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, pseudo-out, gout, spondyloarthropathy, joint infections within the past 5 years), Paget's disease of the spine, pelvis or femur, neuropathic disorders, multiple sclerosis, fibromyalgia, tumors or infections of the spinal cord, or renal osteodystrophy
    3. History or presence on imaging of arthropathy (osteonecrosis, subchondral insufficiency fracture, rapidly progressive OA type 1 or type 2), neuropathic joint arthropathy, hip dislocation (prosthetic hip dislocation is eligible), knee dislocation (patella dislocation is eligible), extensive subchondral cysts, significant bone collapse, significant bone loss, or pathologic fractures
    4. Trauma to the index joint within 3 months prior to the screening visit
    5. Signs or symptoms of carpal tunnel syndrome within 6 months of screening visit
    6. Patient is not a candidate for MRI
    7. Is scheduled for a JR surgery to be performed during the study period or who would be unwilling or unable to undergo JR surgery if one eventually became necessary
    8. History or presence at the screening visit of autonomic neuropathy,diabetic neuropathy, or other peripheral neuropathy, including reflex sympathetic dystrophy
    9. History or diagnosis of chronic autonomic failure syndrome including pure autonomic failure, multiple system atrophy (Shy-Drager syndrome)
    10. History of naproxen intolerance, or existence of a medical condition (eg, high risk of GI bleed, previous ulcer, use of anti-coagulants, or the use of concomitant medication for which naproxen is contraindicated
    11. Known allergy or sensitivity to doxycycline or related compounds, or monoclonal antibodies
    12. Poorly controlled diabetes (defined as any single value of hemoglobin A1c [HbA1c]>9.0%) at the screening visit
    13. Known history of human immunodeficiency virus infection
    14. Known history of ocular herpes simplex virus, herpes simplex virus pneumonia, or herpes simplex virus encephalitis
    15. History of sickle cell disease, including sickle cell anemia and β- thalassemia
    16. Confirmed elevated screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2.5 times the upper limit of normal (ULN)
    17. Resting heart rate of <50 beats per minute (bpm) or >100 bpm (by vital sign assessment or as captured during electrocardiogram [ECG] assessment) at the screening or randomization visits
    18. History or presence of 2nd or 3rd degree heart block, 1st degree heart block with abnormal QRS complex, or bifascicular block by ECG assessment at the screening visit
    19. History or presence of orthostatic hypotension, as defined in Section 8.2.3.4, at the screening, pre-randomization, or randomization visits
    20. History of poorly controlled hypertension, as defined by:
    a. Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg at the screening visit
    b. Systolic blood pressure of 160 mm Hg to 179 mm Hg or diastolic blood pressure
    of 100 mm Hg to 109 mm Hg at the screening visit, AND a history of endorgan damage (including history of left ventricular hypertrophy, heart failure, angina, myocardial infraction, stroke, transient ischemic attack, peripheral arterial disease and moderate to advanced retinopathy [hemorrhages or exudates, papilledema])
    21. Congestive heart failure with NY Heart Classification of stage III or IV (Dolgin 1994)
    22.Transient ischemic attack or cerebrovascular accident within the past 12 months prior to
    the screening visit, or myocardial infarction, or acute coronary syndromes within the past6 months prior to the screening visit
    Se excluirá del estudio a cualquier paciente que cumpla alguno de los siguientes criterios:
    1. Falta de cumplimentación de la escala ENV durante el periodo de pre-aleatorización (4 o más entradas diarias perdidas consecutivas)
    2. Antecedentes o presencia en la visita de selección de enfermedad articular inflamatoria no OA (p. Ej., Artritis reumatoide, lupus eritematoso, artritis psoriásica, pseudogota, gota, espondiloartropatía, infecciones articulares en los últimos 5 años), enfermedad de Paget de la columna vertebral, la pelvis o el fémur, trastornos neuropáticos, esclerosis múltiple, fibromialgia, tumores o infecciones de la médula espinal o osteodistrofia renal
    3. Historia o presencia en la imagen de la artropatía (osteonecrosis,
    fractura de insuficiencia subcondral, OA tipo 1 o tipo rápidamente progresivo
    2), artropatía articular neuropática, luxación de cadera (dislocación de cadera protésica es elegible), la dislocación de la rodilla (dislocación de la rótula es elegible),
    quistes subcondales extensos, colapso óseo significativo, pérdida de hueso significativo
    o fracturas patológicas
    4. Traumatismo en la articulación de referencia en los 3 meses previos a la visita de selección
    5. Signos o síntomas de síndrome del túnel carpiano en los 6 meses previos a la selección
    6. Imposibilidad de someterse a una RM
    7. Artroplastia programada que deba realizarse durante el periodo del estudio, o bien poca disposición o imposibilidad de someterse a una artroplastia si finalmente resulta
    necesario
    8. Antecedentes o presencia de una neuropatía autonómica o diabética, u otra neuropatía periférica, incluida la distrofia simpática refleja, durante la visita de selección
    9. Antecedentes o diagnóstico de síndrome de insuficiencia autonómica crónica, incluidas la insuficiencia autonómica pura y la atrofia multisistémica(síndrome de Shy-Drager)
    10. Antecedentes de intolerancia al naproxeno o la existencia de una condición médica
    (p. ej., alto riesgo de sangrado GI, úlcera previa, uso de anticoagulantes o el uso de concomitante de medicación para la cual el naproxeno está contraindicado)
    11. Alergia o sensibilidad conocidas a la doxiciclina o compuestos relacionados, o anticuerpos monoclonales
    12. Diabetes mal controlada (definida como cualquier valor único de hemoglobina A1c [HbA1c]> 9.0%) en la visita de selección
    13. Historial conocido de infección por el virus de la inmunodeficiencia humana
    14. Antecedentes conocidos del virus del herpes simple ocular, la neumonía por el virus del herpes simple o encefalitis por virus del herpes simple
    15. Historia de la anemia drepanocítica, incluida la anemia de células falciformes y la β-talasemia
    16. Cribado elevado confirmado de alanina aminotransferasa (ALT) o aspartato
    aminotransferasa (AST) ≥2.5 veces el límite superior de la normalidad (ULN)
    17. Frecuencia cardíaca en reposo de <50 latidos por minuto (bpm) o> 100 latidos por minuto (por evaluación del signo vital o capturada durante la evaluación del electrocardiograma [ECG]) en las visitas de cribado o aleatorización
    18. Historia o presencia de bloqueo cardíaco de 2º o 3º grado, bloqueo cardíaco de 1º grado con complejo QRS anormal o bloqueo bifascicular mediante evaluación de ECG en la visita de selección
    19. Historial o presencia de hipotensión ortostática, según se define en la Sección 8.2.3.4, en las visitas de selección, pre-aleatorización o aleatorización
    20. Historial de hipertensión mal controlada, según lo definido por:
    a. Presión arterial sistólica ≥180 mm Hg o presión arterial diastólica ≥110 mm Hg en la visita de selección
    b. Presión arterial sistólica de 160 mm Hg a 179 mm Hg o presión arterial diastólica
    de 100 mm Hg a 109 mm Hg en la visita de selección, y un historial de daño en el órgano endocrino (incluyendo antecedentes de hipertrofia ventricular izquierda, insuficiencia cardíaca, angina, infracción miocárdica, accidente cerebrovascular, ataque isquémico transitorio, enfermedad arterial periférica y retinopatía moderada a avanzada [ hemorragias o exudados, papiledema])
    21. Insuficiencia cardíaca congestiva con NY Heart Classification de estadio III o IV (Dolgin 1994)
    22. Ataque isquémico transitorio o accidente cerebrovascular en los últimos 12 meses antes de la visita de selección o el infarto de miocardio o los síndromes coronarios agudos en los últimos 6 meses anteriores a la visita de selección
    E.5 End points
    E.5.1Primary end point(s)
    1. Change in the WOMAC pain subscale scores from baseline to week 16 in patients treated with fasinumab compared with that of patients treated with placebo.
    2. Change in the WOMAC physical function subscale scores from baseline to week 16 in patients treated with fasinumab compared with that of patients treated with placebo.
    1. Cambio en las puntuaciones de la subescala de dolor del WOMAC desde la visita inicial hasta la semana 16 en los pacientes tratados con fasinumab en comparación con el cambio en los pacientes tratados con placebo.
    2. Cambio en las puntuaciones de la subescala de la funcionalidad física del WOMAC desde la visita inicial hasta la semana 16 en los pacientes tratados con fasinumab en comparación con el cambio en los pacientes tratados con placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At Week 16
    En la semana 16
    E.5.2Secondary end point(s)
    The key secondary endpoints of the study are:
    1. Change in the Patient Global Assessment (PGA) scores from baseline to week 16 in patients treated with fasinumab compared with that of patients treated with placebo
    2. Percentage of patients treated with fasinumab, compared with that of patients treated with placebo, who had a response at week 16, with response defined as an improvement by ≥30% in the WOMAC pain subscale scores
    3. Change in WOMAC pain subscale scores from baseline to week 16 in patients treated with fasinumab, compared with that of patients treated with naproxen
    4. Change in WOMAC physical function subscale scores from baseline to week 16 in patients treated with fasinumab, compared with that of patients treated with naproxen
    5. Change in WOMAC pain subscale scores from baseline to week 52 in patients treated with fasinumab, compared with that of patients treated with placebo
    6. Change in WOMAC physical function subscale scores from baseline to week 52 in patients treated with fasinumab, compared with that of patients treated with placebo
    7. Change in the PGA scores from baseline to week 52 in patients treated with fasinumab compared with that of patients treated with placebo
    8. Change in the PGA scores from baseline to week 16 in patients treated with fasinumab compared with that of patients treated with naproxen

    The safety endpoints in this study are:
    1. Incidence of severe adjudicated arthropathy (AA) (as confirmed by
    adjudication)
    2. Incidence of treatment-emergent adverse events (TEAEs)
    3. Incidence of AA (as confirmed by adjudication)
    4. Incidence of sympathetic nervous system dysfunction (as diagnosed
    after consultation with an appropriate specialist, such as a neurologist
    and/or cardiologist)
    5. Incidence of all-cause joint replacements through week 52 and
    through the follow-up period
    Los criterios de valoración secundarios clave del estudio son:
    1. Cambio en las puntuaciones de la evaluación global del paciente (EGP) desde la visita inicial hasta la semana 16 en los pacientes tratados con fasinumab en comparación con el cambio en los pacientes tratados con placebo
    2. Porcentaje de pacientes tratados con fasinumab que presentaron una respuesta en la semana 16, definida como una mejoría ≥ 30 % en las puntuaciones de la subescala de dolor del WOMAC, en comparación con el porcentaje de pacientes tratados con placebo
    3. Cambio en las puntuaciones de la subescala de dolor del WOMAC desde la visita basal hasta la semana 16 en los pacientes tratados con fasinumab en comparación con el cambio en los pacientes tratados con naproxeno
    4. Cambio en las puntuaciones de la subescala de la funcionalidad física del WOMAC desde la visita basal hasta la semana 16 en los pacientes tratados con fasinumab en comparación con el cambio en los pacientes tratados con naproxeno
    5. Cambio en las puntuaciones de la subescala de dolor del WOMAC desde la visita basal hasta la semana 52 en los pacientes tratados con fasinumab en comparación con el cambio en los pacientes tratados con placebo
    6. Cambio en las puntuaciones de la subescala de la funcionalidad física del WOMAC desde la visita inicial hasta la semana 52 en los pacientes tratados con fasinumab en comparación con el cambio en los pacientes tratados con placebo
    7. Cambio en las puntuaciones de la EGP desde la visita inicial hasta la semana 52 en los pacientes tratados con fasinumab en comparación con el cambio en los pacientes tratados con placebo
    8. Cambio en las puntuaciones de la EGP desde la visita inicial hasta la semana 16 en los pacientes tratados con fasinumab en comparación con el cambio en los pacientes tratados con naproxeno

    Los criterios de valoración de la seguridad de este estudio son los siguientes:
    1. Incidencia de artropatía adjudicada severa (AA) (según lo confirmado por
    validación)
    2. Incidencia de eventos adversos emergentes del tratamiento (TEAE)
    3. Incidencia de AA (según lo confirma la validación)
    4. Incidencia de la disfunción del sistema nervioso simpático (según lo diagnosticado después de consultar con un especialista apropiado, como un neurólogo y / o cardiólogo)
    5. Incidencia de artroplastia por cualquier causa hasta la semana 52 y durante el periodo de seguimiento
    E.5.2.1Timepoint(s) of evaluation of this end point
    At Week 16 and Week 52
    En las semanas 16 y 52
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial5
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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
    Denmark
    Germany
    Hungary
    Lithuania
    Poland
    Romania
    Russian Federation
    South Africa
    Spain
    Ukraine
    United Kingdom
    United States
    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
    The end of study is defined as the last phone contact of the last patient in this study.
    El final del estudio se define como el último contacto telefónico realizado con el último paciente del estudio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    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: 2000
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1640
    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 state184
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1824
    F.4.2.2In the whole clinical trial 3640
    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)
    Treatment after trial completion will be dependent on recommendations from the patient's personal physician.
    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 Decision2017-11-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-25
    P. End of Trial
    P.End of Trial StatusOngoing
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