E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid Arthritis |
Artritis Reumatoide |
|
E.1.1.1 | Medical condition in easily understood language |
Rheumatoid arthritis (RA) is a form of arthritis that causes pain, swelling, stiffness, and loss of function in the joints |
La Artritis Reumatoide es una forma de Artritis que causa dolor, hinchazon, rigidez, y perdida de la funcion de las articulaciones. |
|
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 | 20.0 |
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 |
|
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 |
•To assess the safety, tolerability and efficacy of RO7123520 as adjunctive treatment with Methotrexate (MTX) and anti- Tumor necrosis factor-α (TNF-α) therapy in patients with moderately to severely active RA with an anti-TNF-α inadequate response (Study Parts 1,2, 3) |
•Evaluar la seguridad, la tolerabilidad y la eficacia de RO7123520 como tratamiento complementario con metotrexato (MTX) y tratamiento anti-TNF-α en pacientes con artritis reumatoide (AR) activa moderada o grave con una respuesta inadecuada a los inhibidores de TNF-α (partes 1, 2 y 3 del estudio). |
|
E.2.2 | Secondary objectives of the trial |
•To assess the dose-ranging efficacy of RO7123520 (Study Part 3) •To assess the exposure versus response relationship and immunogenicity of RO7123520 (Study Parts 1,2, 3) |
• Evaluar la eficacia en los distintos intervalos de dosis de RO7123520 (parte 3 del estudio). • Evaluar la inmunogenicidad y la relación entre exposición y respuesta de RO7123520 (partes 1, 2 y 3 del estudio). |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Adult men and women, 18 to 80 years of age (inclusive) - Diagnosis of adult-onset RA as defined by the American College of Rheumatology (ACR) 2010 criteria, for at least 6 months before screening - Moderately to severely active RA as defined by at least 4/28 tender joints and at least 4/28 swollen joints - For Part 2 only: Active synovitis and/or osteitis of the dominant hand/wrist as determined by MRI - Patients must be taking one of the following anti-TNF-α therapies: certolizumab, golimumab, etanercept, adalimumab or approved biosimilars of these, given at an approved and stable dose for at least 12 weeks before randomization, and have experienced in the opinion of the Investigator an inadequate response to anti-TNF-α therapy with a DAS28 => 3.2 - Patients must be taking MTX (PO, SC, or IM) for at least 12 weeks before randomization and must be on a stable dose for at least 4 weeks before randomization (7.5 to 25 mg/week). The dose of MTX is expected to remain stable throughout the study and may be adjusted only for safety reasons. Local standard-of-care should be followed for concomitant administration of folic acid - Patients on glucocorticoids (<= 10 mg/day PO prednisone or equivalent) are permitted if doses are stable within 6 weeks of planned randomization - Patients taking non-steroidal anti-inflammatory drugs (NSAIDs) intermittently (e.g., up to 2-3 times weekly) for short-term relief of pain are allowed, and patients on regular NSAID use (i.e., on stable dose for ≥ 4 weeks) are allowed - Negative pregnancy test at screening and baseline (women only), and agreement to comply with measures to prevent pregnancy and restrictions on sperm donation |
-Hombres y mujeres adultos de 18 a 80 años de edad (ambos inclusive). -Diagnóstico de AR del adulto, definida según los criterios de 2010 del Colegio Estadounidense de Reumatología (American College of Rheumatology, ACR), durante al menos 6 meses antes de la selección. -AR activa moderada o grave, definida como al menos 4/28 articulaciones dolorosas y al menos 4/28 articulaciones inflamadas -Solo en la parte 2: sinovitis u osteítis activa en la mano/muñeca dominante determinada mediante una RMN. -Los pacientes deben estar tomando uno de los tratamientos anti-TNF-α siguientes: certolizumab, golimumab, etanercept, adalimumab o sus biosimilares autorizados, administrados a una dosis aprobada y estable durante al menos 12 semanas antes de la aleatorización y que hayan experimentado, en opinión del investigador, una respuesta inadecuada al tratamiento anti-TNF-α con un índice de actividad de la enfermedad en 28 articulaciones (DAS28) ≥3,2. -Los pacientes deben haber estado tomando MTX (por vía oral, s.c. o i.m.) desde al menos 12 semanas antes de la aleatorización y haber mantenido una dosis estable durante al menos 4 semanas antes de la aleatorización (entre 7,5 y 25 mg/semana). Se espera que la dosis de MTX permanezca estable a lo largo del estudio y solo podrá ajustarse por motivos de seguridad. Se seguirá el tratamiento habitual de su centro para la administración concomitante de ácido fólico. -Se permiten los pacientes tratados con glucocorticoides (≤10 mg/día de prednisona por vía oral o equivalente) si las dosis permanecen estables durante las 6 semanas previas al momento previsto para la aleatorización. -Se permiten pacientes que tomen antiinflamatorios no esteroides (AINE) de forma intermitente (p. ej., hasta 2-3 veces a la semana) para aliviar el dolor puntualmente y pacientes que tomen AINEs de forma regular (es decir, a una dosis estable durante ≥ 4 semanas). -Prueba de embarazo negativa en la selección y al inicio (solo mujeres), y aceptar la adopción de las medidas para evitar embarazos y las restricciones a la donación de semen. |
|
E.4 | Principal exclusion criteria |
- Currently receiving concomitant treatment with sulfasalazine or leflunomide - Patients currently on IV infliximab or an approved IV biosimilar of it are excluded - Parenteral glucocorticoids administration (IM, IV) of ≥50 mg within 6 weeks prior to planned randomization, or ≤50 mg within 4 weeks prior to planned randomization, or scheduled parenteral administrations during the study - Joints injected with intra-articular glucocorticoids or hyaluronic acid within 6 weeks prior to planned randomization - Active inflammatory disease of the joints not related to RA - Systemic autoimmune disease other than RA - Juvenile idiopathic arthritis or juvenile RA and/or RA developed before the age of 16 - Active fibromyalgia that makes appropriate assessment of RA disease activity challenging in the opinion of the Investigator - RA patients functional status class IV according to the American College of Rheumatology (ACR) 1991 criteria (i.e., largely or wholly incapacitated permitting little or no self-care, such as being bedridden or confined to wheelchair) - Patients with severe chronic or recurrent viral, bacterial, parasitic or fungal infections - History of active hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection - Any identified confirmed congenital or acquired immunodeficiency - Abnormal laboratory test results - Other unstable somatic diseases (apart from RA) that can increase the probability of adverse events during the study or can influence the estimation of symptom manifestation of RA; mask, enhance or alter the symptoms of RA or cause clinical or laboratory symptoms similar to that of RA - Major surgery within 28 days prior to randomization, or requiring major surgery (e.g., elective joint replacement surgery) during the trial - Any mental disorder - Myocardial infarction within less than 6 months prior to participation in the study - Severe central or peripheral nervous system diseases - Chronic drug or alcohol abuse - Known hypersensitivity to any components of the medications used in the study - Acute forms of any infectious diseases or history of chronic infections with severe clinical manifestations - Presence of malignant neoplasm, with the exception of adequately treated basal cell carcinoma and cervical carcinoma in situ and any malignancy with complete remission of more than 5 years - German sites: Patients who are institutionalized due to regulatory or juridical order - German sites: Patients who are occupationally or medically dependent on the Sponsor, the Investigator, or the medical site |
-Tratamiento concomitante en curso con sulfasalazina o leflunomida. -Se excluirá a los pacientes que estén siendo tratados con infliximab i.v. o un medicamento biosimilar aprobado por vía i.v.. -Administración parenteral de glucocorticoides (i.m., i.v.) de ≥50 mg en las 6 semanas o ≤50 mg en las 4 semanas previas al momento previsto para la aleatorización, o bien administraciones parenterales programadas durante el estudio. -Articulaciones donde se hayan inyectado glucocorticoides intraarticulares o acido hialurónico en las 6 semanas previas al momento previsto para la aleatorización. -Una o varias enfermedades inflamatorias activas de las articulaciones sin relación con la AR -Enfermedad autoinmunitaria sistémica distinta de la AR -Artritis idiopática juvenil o AR juvenil, o bien AR surgida antes de los 16 años. -Fibromialgia activa que dificulte la evaluación adecuada de la actividad de la AR por parte del investigador. -Estado funcional de clase IV de los pacientes con AR según los criterios de la ACR de 1991 (es decir, incapacitado totalmente o en gran medida, de manera que no puede cuidarse a sí mismo o apenas puede hacerlo, por ejemplo por estar confinado a la cama o a una silla de ruedas). -Pacientes con infecciones graves crónicas o recurrentes víricas, bacterianas, parasitarias o fúngicas. -Antecedentes de infección activa por el virus de la hepatitis B (VHB), el virus de la hepatitis C (VHC) o el virus de la inmunodeficiencia humana (VIH). -Cualquier inmunodeficiencia detectada y confirmada de carácter congénito o adquirido. -Valores analíticos anómalos -Otras enfermedades somáticas inestables distintas de la AR que puedan aumentar la probabilidad de acontecimientos adversos durante el estudio o influenciar la estimación de la manifestación de los sintomas de la AR, enmascarar, potenciar o alterar los síntomas de AR o causar síntomas clínicos o analíticos similares a los de la AR. -Cirugía mayor en los 28 días previos a la aleatorización o necesidad de cirugía mayor (p. ej., cirugía de artroplastia programada) durante el ensayo. -Cualquier trastorno mental -Infarto de miocardio en un plazo inferior a los 6 meses anteriores a la participación en el estudio. -Enfermedades graves del sistema nervioso central o periférico. -Toxicomanía o alcoholismo crónicos. -Hipersensibilidad conocida a cualquiera de los componentes de los medicamentos utilizados en el estudio. -Formas agudas de cualquier enfermedad infecciosa o antecedentes de infecciones crónicas con manifestaciones clínicas graves -Presencia de neoplasia maligna, excepto carcinoma basocelular y carcinoma cervicouterino in situ tratados adecuadamente, así como cualquier neoplasia maligna con remisión completa de más de 5 años. -Centros alemanes: pacientes internados debido a una orden reglamentaria o judicial. -Centros alemanes: pacientes que sean ocupacional o médicamente dependientes del promotor, el investigador o el centro clínico. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Incidence of adverse events 2. Incidence of ECG, vital signs and laboratory abnormalities 3. Assessment of bone remodeling and cartilage markers 4. Assessment of blood cell markers 5. Anti-drug antibodies (ADA) 6. Bone mineral density by dual energy X-ray absorptiometry (DEXA) scans 7. Proportion of patients achieving an ACR50 response at Week 12 |
1. Incidencia de los acontecimientos adversos 2.Incidencia de ECGs, signos vitales y anomalias de laboratorio 3.Evaluación de la remodelación ósea y de los marcadores de los cartílagos 4. Evaluación de los marcadores de células sanguíneas 5.Anticuerpos antifármaco (AAF) 6.Densidad mineral ósea mediante exploraciones de absorciometría de rayos X de doble energía (DEXA) 7.Proporción de pacientes que logran una respuesta ACR50 en la semana 12 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-2. Up to 36 weeks (including German sites) 3. Baseline (Day 1), Week 4, Week 12, Week 16, Week 24, and Week 28 4. Baseline, Week 2, Week, 4, Week, 6, Week 12, Week, 16, Week 24, and Week 28 5. Baseline, Week 12, Week 16, and Week 28 6. Screening (Day -7 to -1), Week 12, and Week 24 7. Week 12 |
1-2 Hasta un maximo de 36 semanas (incluyendo a los centros alemanes) 3. Basal (dia 1), semana 4, semana 12, semana 16, semana 24 y semana 28 4. Basal, semana 2, semana 4, semana 6, semana 12, semana 16, semana 24 y semana 28 5. Basal, semana 12, semana 16 y semana 28 6. Screening (dia -7 a -1) semana 12, semana 24 7. Semana 12 |
|
E.5.2 | Secondary end point(s) |
1. Change from baseline in Clinical Disease Activity Index (CDAI) Score at Week 12 2. Change from baseline in Disease Activity Score (DAS28) at Week 12 3. Proportion of patients achieving DAS28 remission at Week 12 4. Proportion of patients achieving CDAI remission at Week 12 5. Proportion of patients achieving an ACR20 response at Week 12 6. Proportion of patients achieving an ACR70 response at Week 12 7. Simple Disease Activity Index (SDAI) Score at Week 12 8. Change from baseline in the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 9. Serum and synovial fluid concentration of RO7123520 |
1. Cambio desde el inicio en la puntuación de CDAI en la semana 12 2-Cambio desde el inicio en la DAS28 en la semana 12 3. Proporción de pacientes que logran una remisión según DAS28 en la semana 12 4. Proporción de pacientes que logran una remisión según CDAI en la semana 12 5. Proporción de pacientes que logran una respuesta ACR20 en la semana 12 6. Proporción de pacientes que logran una respuesta ACR70 en la semana 12 7. Puntuación en el Índice simple de actividad de la enfermedad (Simple Disease Activity Index, SDAI) en la semana 12 8. Cambio desde el inicio en el Índice de discapacidad del Cuestionario de evaluación de la salud de Stanford (Stanford Health Assessment Questionnaire Disability Index, HAQ-DI) en la semana 12 9. Concentracion en suero y en fluido sinovial de RO7123520 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2. Baseline and Week 12 3-7. Week 12 8. Baseline and Week 12 9. Baseline, Week 12, and Week 24 (for synovial fluid ); Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, and Week 28 (for serum) |
1-2. Basal y semana 12 3-7. Semana 12 8. Basal y semana 12 9. Basal, semana 12 y semana 24 (para el fluido sinovial); Basal, semana 2, semana 4, semana 8, semana 12, semana 16, semana 20, semana 24, y semana 28 (para el suero) |
|
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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
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 | 5 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
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 |
Argentina |
Austria |
Colombia |
Germany |
Guatemala |
Italy |
Mexico |
Peru |
Poland |
Spain |
United Kingdom |
United States |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 22 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 22 |