E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid Arthritis (RA) |
Artritis reumatoide (AR) |
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E.1.1.1 | Medical condition in easily understood language |
Rheumatoid Arthritis |
Artritis reumatoide |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to compare the safety and efficacy of multiple doses of ABT-494 versus placebo in subjects with moderately to severely active RA on stable background MTX therapy who have not shown an adequate response to MTX alone. |
El objetivo principal es comparar la seguridad y la eficacia de varias dosis de ABT-494 en comparación con placebo en pacientes con AR activa moderada o grave que reciben un tratamiento de base estable con MTX que presentaron una respuesta inadecuada a la monoterapia con MTX. |
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E.2.2 | Secondary objectives of the trial |
Not applicable |
No procede |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adult male or female, at least 18 years old. 2. Diagnosed with RA based on either the 1987-revised ACR classification criteria or the 2010 American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) criteria for ? 3 months. 3. Have active RA as defined by the following minimum disease activity criteria: ? ? 6 swollen joints (based on 66 joint counts) at Screening and Baseline Visits. ? ? 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits. ? hsCRP > Upper Limit of Normal (ULN) OR positive for both rheumatoid factor and anti-CCP at Screening. 4. Subjects must have been receiving oral or parenteral methotrexate therapy ? 3 months and on a stable prescription of 7.5 to 25 mg/week for at least 4 weeks prior to Baseline Visit. Subjects should also be on a stable dose of folic acid (or equivalent) for at least 4 weeks prior to Baseline Visit. Subjects should continue with their stable doses of methotrexate and folic acid throughout the study. 5. Except for MTX, subjects must have discontinued all oral DMARDs prior to Baseline Visit as specified below or for at least five times the mean terminal elimination half-life of a drug, whichever is longer: ? ? 4 weeks prior to Baseline Visit for minocycline, penicillamine, sulfasalazine, hydroxychloroquine, chloroquine, azathioprine, gold formulations, cyclophosphamide ? ? 8 weeks prior to Baseline Visit for leflunomide if no elimination procedure was followed, or adhere to a washout procedure (i.e., 11 days washout with colestyramine, or 30 days washout with activated charcoal) 6. Subject has a negative TB Screening Assessment. If the subject has evidence of a latent TB infection, the subject must initiate and complete a minimum of 2 weeks (or per local guidelines, whichever is longer) of an ongoing TB prophylaxis or have documented completion of a full course of TB prophylaxis, prior to Baseline Visit. 7. Subjects can be taking non-steroidal anti-inflammatory drugs (NSAIDS), acetaminophen, oral corticosteroids (equivalent to prednisone ? 10 mg), or inhaled corticosteroids at a stable dose for at least 4 weeks prior to Baseline Visit for stable medical conditions and should be kept at a stable dose throughout the study. NSAIDs andacetaminophen, taken PRN are allowed but may not be taken 24 hours prior to any study visit. Oral and inhaled corticosteroids taken PRN are NOT allowed. The use of tramadol, codeine, and propoxyphene is discouraged, but subjects may take PRN doses except 24 hours prior to any study visit. 8. Subjects must have discontinued high potency opiates including (but not limited to): oxycodone, oxymorphone, fentanyl, levorphanol, buprenorphine, methadone, hydromorphone, and morphine at least 4 weeks prior to Baseline Visit. |
1. Pacientes adultos de ambos sexos, de 18 años de edad como mínimo. 2. Se les ha diagnosticado AR según los criterios de clasificación de 1987 del ACR o los criterios 2010 del Colegio Estadounidense de Reumatología/Liga Europea Contra el Reumatismo (American College of Rheumatology (ACR)/European League against Rheumatism (EULAR)) durante >= 3 meses. 3. Tienen AR activa, definida por los siguientes criterios mínimos de enfermedad activa: ? 6 articulaciones inflamadas (según los recuentos de 66 articulaciones) o más en las visitas de selección e inicial. ? 6 articulaciones dolorosas (según los recuentos de 68 articulaciones) o más en las visitas de selección e inicial. ? PCR-as > límite superior de la normalidad (LSN) O positivo para factor reumatoide y anti-CCP en la selección. 4. Los pacientes tienen que haber recibido tratamiento oral o parenteral con metotrexato durante >= 3 meses con una prescripción estable de 7,5 a 25 mg/semana durante al menos 4 semanas antes de la visita inicial. Los pacientes también deben recibir una dosis estable de ácido fólico (o equivalente) durante al menos 4 semanas antes de la visita inicial. Además, deben seguir recibiendo sus dosis estables de MTX y ácido fólico durante todo el estudio. 5. Excepto MTX, los pacientes tienen que haber suspendido todos los FARME orales antes de la visita inicial, tal como se especifica a continuación, o al menos cinco veces la semivida media de eliminación terminal de cada fármaco, el período más largo entre ambos. ? >= 4 semanas anteriores a la visita inicial en caso de minociclina, penicilamina, sulfasalazina, hidroxicloroquina, cloroquina, azatioprina, formulaciones de oro o ciclofosfamida. ? >= 8 semanas antes de la visita inicial para la leflunomida si no se siguió un procedimiento de eliminación, o se debe seguir un procedimiento de reposo farmacológico (es decir, reposo farmacológico de 11 días con colestiramina o 30 días de reposo farmacológico con carbón activado). 6. El paciente tiene un resultado negativo en la prueba de detección de TB. Si el paciente tiene indicios de TB latente, debe iniciar y completar como mínimo 2 semanas (o siguiendo las normas locales, el período más largo de ambos) de profilaxis continuada para la TB o debe demostrarse que ha terminado un ciclo completo de profilaxis de la TB antes de la visita inicial. 7. Los pacientes pueden estar tomando fármacos antinflamatorios no esteroideos (AINE), paracetamol, corticoesteroides orales (equivalentes a <= 10 mg de prednisona) o inhalados en dosis estables durante al menos 4 semanas antes de la visita inicial para problemas médicos estables y la dosis debe mantenerse estable a lo largo del estudio. Se permiten los AINE, andacetaminofeno, tomados a demanda pero no 24 horas antes de cualquier visita del estudio. NO se permiten los corticoesteroides orales o inhalados tomados a demanda. Se desaconseja el uso de tramadol, codeína y propoxifeno aunque los pacientes pueden tomar dosis a demanda salvo las 24 horas previas a cualquier visita del estudio. 8. Los pacientes deben haber suspendido la administración de opiáceos de gran potencia, incluidos (entre otros): oxicodona, oximorfona, fentanilo, levorfanol, buprenorfina, metadona, hidromorfona y morfina, al menos 4 semanas antes de la visita inicial. |
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E.4 | Principal exclusion criteria |
1. Female who is pregnant or breastfeeding. 2. Prior exposure to JAK inhibitor (e.g., tofacitinib, baricitinib). 3. Prior exposure to any investigational or approved biologic RA therapy. 4. Receipt of any investigational drug of chemical or biologic nature within a minimum of 30 days or 5 half-lives of the drug (whichever is longer) prior to Baseline Visit. 5. Current or expected need of other immunosuppressant medications, except methotrexate. Use of oral intake of > 10 mg prednisone/day or equivalent corticosteroid therapy (see inclusion criterion 7). 6. Subject has been treated with intra-articular or parenteral administration of corticosteroids in the preceding 8 weeks prior to the Baseline Visit. 7. Screening laboratory values meeting the following criteria: ? Serum aspartate transaminase (AST) or alanine transaminase (ALT) > 1.5 × ULN ? Estimated glomerular filtration rate (eGRF) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73 m2 ? Total white blood cell count (WBC) < 3,000/µL ? Absolute neutrophil count (ANC) < 1,200/µL ? Platelet count < 100,000/µL ? Absolute lymphocytes count < 750/ µL ? Hemoglobin < 9 gm/dL |
1. Mujer que esté embarazada o en período de lactancia materna. 2. Han recibido anteriormente un inhibidor de la cinasa JAK (p. ej., tofacitinib o baricitinib). 3. Exposición previa a cualquier tratamiento biológico aprobado o en investigación para la AR. 4. Reciben un fármaco en investigación de naturaleza biológica o química en un período mínimo de 30 días o 5 semividas del fármaco (el período más largo de ellos) antes de la visita inicial. 5. Necesitan actualmente o se espera que necesiten otros medicamentos inmunodepresores, excepto metotrexato. Reciben una dosis oral de prednisona > 10 mg/día o de un corticoesteroide equivalente (véase el criterio de inclusión 7). 6. El paciente ha recibido corticoesteroides en infiltraciones intrarticulares o por vía parenteral en las 8 semanas previas a la visita inicial. 7. Los valores de los análisis de selección cumplan los siguientes criterios: ? aspartato aminotransferasa (AST) o alanina aminotransferasa (ALT) > 1,5 veces el LSN en suero ? Filtración glomerular estimada (FGe) según la fórmula simplificada de 4 variables de la Modificación de la dieta en la nefropatía (Modification of Diet in Renal Disease, MDRD) < 40 ml/min/1,73 m2 ? Recuento total de leucocitos < 3000/?l ? Recuento absoluto de neutrófilos (RAN) < 1200/?l ? Recuento de plaquetas <100.000 /?l ? Recuento absoluto de linfocitos < 750/?l ? Hemoglobina < 9 g/dl |
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E.5 End points |
E.5.1 | Primary end point(s) |
ACR20 response rate. |
Tasas de respuesta ACR20 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are ACR50/70 response rates at Week 12, the proportion of subjects achieving low disease activity (LDA) or clinical remission (CR) based on DAS28 [CRP] and CDAI criteria at Week 12, and the proportion of subjects achieving CR based on DAS28 [CRP] and CDAI criteria at Week 12. |
Los criterios de valoración secundarios de este estudio son Tasas de respuesta ACR50/70 en la semana 12, la Proporción de pacientes que alcancen una actividad baja de la enfermedad (LDA) o remisión clínica (RC) según puntuación DAS28 [PCR] y criterios CDAI en la semana 12, y la Proporción de pacientes que alcanzan la RC basada en una puntuación DAS28 [PCR] y criterios CDAI en la semana 12. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 6 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Chile |
European Union |
Israel |
Mexico |
Puerto Rico |
Russian Federation |
Serbia |
South Africa |
Turkey |
Ukraine |
United States |
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E.8.7 | Trial 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
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The end-of-study is defined as the date of the last subject's last visit or the actual date of follow-up contact, whichever is later. |
El final del estudio se define como la fecha de la última visita del último paciente o la fecha real del contacto de seguimiento, lo que ocurra más tarde. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |