E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid arthritis |
Artritis reumatoide |
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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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and the systemic and local tolerability of repeated doses of BI 655064 (120 mg/mL in buffer solution for injection), administered s.c. at doses of 80, 120 and 180 mg every week in healthy volunteers (HVs) (treatment duration 4 weeks per dose group) and 120 and 180 mg every week in rheumatoid arthritis (RA) patients with prior inadequate response to methotrexate (MTX) therapy (treatment duration 12 weeks per dose group). |
Evaluar la seguridad y la tolerabilidad local y sistémica de dosis repetidas de BI 655064 (120 mg/ml en solución tampón para inyección), administradas por vía s.c. a dosis semanales de 80, 120 y 180 mg a voluntarios sanos (HV) (duración del tratamiento: 4 semanas por grupo de dosis) y a dosis semanales de 120 y 180 mg a pacientes con artritis reumatoide (RA) con una respuesta previa insuficiente al tratamiento con metotrexato (MTX) (duración del tratamiento: 12 semanas por grupo de tratamiento). |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate PK and PD parameters of BI 655064 administered in repeated doses in HVs and in RA patients 2. To evaluate the clinical effect of BI 655064 after 12 weeks of treatment with two different doses (120 and 180mg s.c. ew) in RA patients with prior inadequate response to MTX ? establishing the proof of concept in RA. |
1. Evaluar parámetros farmacocinéticos y farmacodinámicos para BI 655064 administrado a dosis repetidas a HV y pacientes con RA 2. Evaluar el efecto clínico de BI 655064 después de un período de tratamiento de 12 semanas con dos dosis diferentes (120 mg y 180 mg s.c./semana) en pacientes con RA con una respuesta previa insuficiente a MTX ? establecer la prueba de concepto en la RA. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part 1 (HVs): 1. Healthy males and females according to the investigator?s assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests 2. Age >= 18 and <= 60 years 3. Body Mass Index >= 18.5 and <= 29.9 kg/m2 4. Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation 5. Female subjects who meet any of the following criteria from at least 30 days before the first study drug administration and until 30 days after trial completion: - using adequate contraception, e.g. any of the following methods plus condom: implants, injectables, combined oral contraceptives, intrauterine device (IUD) - sexually abstinent - have a vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) - surgically sterilised (including hysterectomy) - postmenopausal defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of follicle stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory)
Part 2 (RA Patients): 1. Age >= 18 and <= 70 years 2. Patients classified as having RA according to the 1987 ACR Classification Criteria 3. <= 5 years from RA diagnosis to screening 4. Insufficient clinical response to methotrexate defined as moderate/high active disease after oral or s.c MTX treatment given continuously for at least 3 months and for the last 6 weeks before screening at a stable weekly dose >=15mg. 5. Moderate or highly active disease defined as DAS28 4v-CRP >= 3.5 with >= 6 tender and >= 6 swollen joints at screening and confirmed by >= 6 tender and >= 6 swollen joints only at randomisation visit (Visit 2) 6. Serum CRP level >= 1.0 mg/dL at screening 7. Anti-CCP2 positivity as per the limits of used assay 8. Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation |
Parte 1 (HV): 1. Hombres y mujeres sanos de acuerdo con la evaluación del investigador basada en los criterios siguientes: historia clínica completa y exploración física, constantes vitales (BP, PR), ECG de 12 derivaciones y pruebas analíticas 2. Edad >= 18 y <= 60 años 3. Índice de masa corporal >= 18,5 y <= 29,9 kg/m2 4. Consentimiento informado por escrito firmado y fechado antes de la inclusión en el estudio conforme a la GCP y la legislación local 5. Las participantes deben cumplir alguno de los criterios siguientes desde un mínimo de 30 días antes de la primera administración del fármaco del estudio hasta 30 días después de finalizar el estudio: - uso de un método anticonceptivo adecuado, es decir, alguno de los métodos siguientes combinado con preservativos: implantes, inyectables, anticonceptivos orales combinados, dispositivo intrauterino (IUD) - abstinencia sexual - tener una pareja sexual sometida a vasectomía (la vasectomía debe remontarse al menos a 1 año antes de la inclusión) - haber sido sometida a esterilización quirúrgica (incl. histerectomía) - hallarse en período postmenopáusico definido como una amenorrea espontánea con una duración superior a 1 año [en casos dudosos una muestra de sangre con niveles simultáneos de hormona foliculoestimulante (FSH) superior a 40 U/l y de estradiol inferior a 30 ng/l es confirmatoria]
Parte 2 (pacientes con RA): 1. Edad >= 18 y <= 70 años 2. Pacientes diagnosticados de RA según los Criterios de clasificación de la ACR de 1987 3. ? 5 años entre el diagnóstico de la RA y la selección 4. Respuesta clínica insuficiente a metotrexato definida como una enfermedad con actividad moderada/alta después de un tratamiento con MTX administrado por vía oral o s.c de forma continuada durante un mínimo de 3 meses y durante las 6 semanas anteriores a la selección a una dosis semanal estable de ?15 mg. 5. La enfermedad con actividad moderada o alta se define como un DAS28 4v-CRP de >= 3,5 con >= 6 articulaciones dolorosas y >= 6 articulaciones tumefactas en el momento de la selección y confirmada con >= 6 articulaciones dolorosas y >= 6 articulaciones tumefactas sólo en la visita de aleatorización (visita 2) 6. Nivel sérico de CRP >= 1,0 mg/dl en el momento de la selección 7. Resultado positivo para anti-CCP2 según los límites de la prueba utilizada 8. Consentimiento informado por escrito firmado y fechado antes de la inclusión en el estudio conforme a la GCP y la legislación local |
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E.4 | Principal exclusion criteria |
Part 1 (HVs): 1. Any finding in the medical examination (including BP, PR or ECG) deviating from normal and judged clinically relevant by the investigator 2. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance 3. Any evidence of a concomitant disease judged clinically relevant by the investigator 4. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders 5. Diseases of the central nervous system (such as epilepsy), other neurological disorders or psychiatric disorders 6. History of relevant orthostatic hypotension, fainting spells, or blackouts 7. Chronic or relevant acute infections 8. History of relevant allergy/hypersensitivity (including allergy to the trial medication or its excipients) 9. Intake of drugs with a long half-life (>24 hours) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication 10. Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial 11. Participation in another trial with investigational drug administration within 60 days prior to administration of trial medication 12. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes/day) 13. Alcohol abuse (consumption of more than 140 g/week in females and 210 g/week in males) 14. Drug abuse or positive drug screen 15. Blood donation (more than 100 mL within 30 days prior to administration of trial medication or intended during the trial) 16. Intention to commence new exercise regimen within one week prior to administration of trial medication or during the trial 17. Inability to comply with dietary regimen of trial site 18. Subject is assessed by the investigator as unsuitable for inclusion e.g. considered not able to understand and comply with study requirements or has a condition that would not allow safe participation in the study 19. Chronic or relevant acute infections, including but not limited to HIV, Hepatitis B and C and tuberculosis (including a history of clinical TB and/or a positive QuantiFERON TB-Gold test) For female subjects: 20. Positive pregnancy test, pregnancy or plans to become pregnant within 30 days after study completion 21. Lactation Part 2 (RA patients): Part 1 exclusion criteria 19 ? 21 plus: 1. Current or previous use of an approved biologic agent (either anti-TNF or with other mechanism of action, e.g. anakinra, abatacept, tocilizumab or rituximab) or new oral compound (e.g. JAK inhibitors, PTK inhibitors or CXC blockers) for treating RA 2. Current or previous participation in a clinical trial testing an investigational drug for RA 3. DAS28 < 3.2 in at least 2 occasions during the last 6 months before screening Note: DAS28 results during the last 6 months before screening visit will be provided as source documents if available. However, patients with less than 2 DAS28 results available during this time will not be excluded. 4. RA patients with severe disability (functional class IV) or with confirmed severe systemic manifestations e.g. known amyloidosis, Felty´s syndrome, lymphoproliferative disorders, rheumatoid vasculitis 5. Treatment with any standard DMARD except MTX (including but not limited to sulfasalazine, leflunomide, hydroxychloroquine, D-penicillamine, azathioprine, cyclosporin, gold salts) continuing after randomisation Note: If patient is on treatment with any other standard DMARD (except MTX) at the time of the screening visit, this should be tapered and stopped before randomisation. MTX should be continued during the screening period at a stable dose between 15-25mg per week. 6. Impaired hepatic function, defined as serum AST/ALT, bilirubin or alkaline phosphatase levels > 2 x ULN 7. Impaired renal function defined as calculated creatinine clearance < 50ml/min 8. Pre-existing blood dyscrasias e.g. bone marrow hypoplasia, significant anaemia, leucopenia or thrombocytopenia 9. Hypersensitivity to MTX or any of its excipients 10. Previous intolerance to MTX as the main cause for stopping treatment (instead of lack of efficacy) 11. Any active or suspected malignancy or history of documented malignancy, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix. |
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E.5 End points |
E.5.1 | Primary end point(s) |
There are no primary safety, PK, PD endpoints in a statistical sense in this study.
Primary Endpoint(s) of efficacy - Part 2: - ACR20 response rate |
En este estudio no existe una variable principal en un sentido estadístico en cuanto a seguridad, PK o PD.
Variable principal de eficacia - Parte 2: - Tasas de respuesta ACR20 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At Week12 (Day 85) from the initiation of study treatment |
Semana 12 (día 85) respecto al inicio del tratamiento del estudio |
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E.5.2 | Secondary end point(s) |
- ACR50 and 70 response rates - EULAR Response Criteria (DAS28 4v-CRP) - Percentage of patients with a decrease in DAS28 4v-CRP of >1.2 |
- Tasas de respuesta ACR50 y 70 - Criterios de respuesta EULAR (DAS28 4v-CRP) - Porcentaje de pacientes con una disminución del DAS28 4v-CRP de >1,2 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- At Week12 (Day 85) - At Week12 (Day 85) - At Week 12 (Day 85) compared to baseline |
- en la semana 12 (día 85) - en la semana 12 (día 85) - en la semana 12 (día 85) en comparación con el momento basal |
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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 | Yes |
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 | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Multiple Rising Doses (MRD) in Healthy Volunteers |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
Multiple rising dose for Part 1 |
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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 | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 12 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 15 |
E.8.9.2 | In all countries concerned by the trial days | 0 |