| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate-to-severely active ulcerative colitis |
| Colitis ulcerosa activa de moderada a grave |
|
| E.1.1.1 | Medical condition in easily understood language |
| Moderate-to-severely active ulcerative colitis |
| Colitis ulcerosa activa de moderada a grave |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
| 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 prove the concept of clinical activity of BI 655130 in patients with moderate-to-severely active ulcerative colitis who have failed previous biologic treatments and to identify efficacious and safe dose regimens in Part 1 (Phase II) |
| - Demostrar el concepto de actividad clínica de BI 655130 en pacientes con colitis ulcerosa activa de moderada a grave que no han respondido al tratamiento previo con fármacos biológicos e identificar pautas posológicas eficaces y seguros en la Parte 1 (Fase II) |
|
| E.2.2 | Secondary objectives of the trial |
- To confirm efficacy and safety of BI 655130 in patients with moderate-to-severely active ulcerative colitis who have failed previous biologic treatments in Part 2 (Phase III)
- To provide, along with induction study 1368-0018 and the run-in cohort of 1368- 0020, the target population to be evaluated in the randomised withdrawal study 1368- 0020. |
- Confirmar la eficacia y seguridad de BI 655130 en pacientes con colitis ulcerosa activa de moderada a grave que no han respondido al tratamiento previo con fármacos biológicos en la parte 2 (Fase III)
- Proporcionar, junto con el estudio de inducción 1368-0018 y la cohorte de preinclusión de 1368-0020, la población objetivo que se evaluará en el estudio de retirada aleatorizado 1368-0020. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 18 - 75 years, at date of signing informed consent, males or females
2. Diagnosis of ulcerative colitis ≥ 3 months prior to screening by clinical and endoscopic evidence corroborated by a histopathology report
3. Moderate to severe activity (total MCS 6 to 12 AND mESS ≥ 2 within 7-28 days prior to first dose)
4. Endoscopic activity extending proximal to the rectum (≥ 15 cm from anal verge)
5. Demonstrated in the past inadequate response or loss of response or have had unacceptable side effects with approved doses of TNFα antagonists (infliximab, adalimumab, golimumab) and / or vedolizumab
6. May be receiving a therapeutic dose of the following:
- Oral 5-ASA compounds, provided that dose has been stable for at least the 4 weeks immediately prior to randomisation, and/or
- Oral corticosteroids (≤ 20 mg per day of prednisone or equivalent), provided that dose has been stable for the 2 weeks immediately prior to randomisation, and/or
- Oral budesonide (≤ 9 mg per day ), provided that dose has been stable for the 2 weeks immediately prior to randomisation, and/or
- Azathioprine, 6-MP or methotrexate, provided that dose has been stable for the 8 weeks immediately prior to randomisation.
- Probiotics (e.g. S. boulardii) provided that dose has been stable for the 4 weeks immediately prior to randomisation.
7. Patients with extensive colitis or pancolitis of >10 years duration or family history of colorectal cancer or personal history of increased colorectal cancer risk must have had a negative colorectal cancer screening within <1 year prior to enrolment (otherwise to be done during screening colonoscopy).
8. Women of childbearing potential (WOCBP) and men able to father a child must be ready to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly.
9. Signed and dated written informed consent for 1368.5, in accordance with GCP and local legislation prior to admission into the trial |
1. Pacientes de ambos sexos, de 18 a 75 años en la fecha de la firma del consentimiento informado
2. Diagnóstico de colitis ulcerosa ≥ 3 meses antes de la selección a través de indicios clínicos y endoscópicos corroborados mediante informe histopatológico
3. Actividad de moderada a grave (MCS [puntuación de la Clínica mayo, Mayo Clinical Score] total de 6 a 12 Y mESS [subpuntuación endoscópica modificada, modified Endoscopic Subscore] ≥ 2 en los 7-28 días antes de la primera dosis)
4. Actividad endoscópica extensiva próxima al recto (≥ 15 cm del borde anal)
5. Demostrado en el pasado respuesta inadecuada, o pérdida de respuesta o ha tenido efectos secundarios inaceptables con dosis autorizadas de antagonistas de TNFα (infliximab, adalimumab, golimumab)y/o vedolizumab
6. Puede estar tomando una dosis terapéutica de lso siguientes:
- Compuestos 5-ASA orales, simpre que la dosis haya permanecido estable durante al menos las 4 semanas inmediatamente previas a la randomización, i/o
- Corticosteroides orales (≤ 20 mg al dia de prednisona o equivalente), siempre que la dosis haya permanecido estable durante las 2 semanas inmediatamente previas a la randomización, i/o
- Budesonida oral (≤ 9 mg al dia), siempre que la dosis haya permanecido estable durante las 2 semanas inmediatamente previas a la randomización, i/o
- Azatioprina, 6-MP o metotrexato, siempre que la dosis haya permanecido estable durante las 8 semanas inmediatamente previas a la randomización.
- Probioticos (p.e. S. boulardii), siempre que la dosis haya permanecido estable durante las 4 semanas inmediatamente previas a la randomización.
7. Pacientes con colitis extensiva o pancolitis de > 10 años de duración o historial familiar de cáncer colorectal o historial personal de incremento del riesgo de cáncer colorectal deberán haber tenido un screening negativo para cáncer colorrectal <1 antes de la inclusión (sinó se realizará durante la colonoscopia de la selección)
8. Mujeres con potencial de quedarse embarazadas y hombres capces de concebir un hijo deben esatr preparados para usar métodos anticonceptivos de alta eficacia según ICH M3 (R2) que resultan en una tasa de fallo de menos de 1% por año si se usan de forma consistente y correcta.
9. Consentimiento informado para el ensayo 1368.5 por escrito ,firmado y fechado, de acuerdo con las GCP y la legislación local antes de la admisión al ensayo. |
|
| E.4 | Principal exclusion criteria |
1. Evidence of abdominal abscess at screening
2. Evidence of fulminant colitis or toxic megacolon at screening
3. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
4. Treatment with:
•any non-biologic medication (e.g. cyclosporine, tacrolimus or mycophenolate mofetil, intavenous corticosteroids, tofacitinib),
•any biologic treatment with a TNFα antagonist (adalimumab, infliximab, golimumab) or vedolizumab within 8 weeks prior to randomisation
•rectal 5-ASA, parenteral or rectal corticosteroids (incl. budesonide) within 2 weeks prior to screening
•any investigational non-biologic drug for UC (including but not limited to JAK inhibitors, S1P modulators) within 30 days prior to randomisation
•any investigational biologic for UC (including but not limited to ustekinumab and other IL-23 inhibitors) within 12 weeks prior to randomisation (except etrolizumab: within 8 weeks prior to randomisation)
•any prior exposure to BI 655130, natalizumab or rituximab
5. Positive stool examinations for C. difficile or other intestinal pathogens < 30 days prior to screening
6. have had previous surgery or are anticipated to require surgical intervention for UC
7. Evidence of colonic moderate/severe mucosal dysplasia or colonic adenomas, unless properly removed
8. Primary sclerosing cholangitis
9. Faecal transplant ≤ 6 months before screening
10. Increased risk of infectious complications (e.g. recent pyogenic infection, any congenital
or acquired immunodeficiency (e.g. HIV), past organ or stem cell transplantation)
11. Live or attenuated vaccination within 6 weeks prior to screening
12. Active or latent TB: Patients with a positive TB test within one month of screening are
excluded:
•A positive QuantiFERON TB (Patients with suspected false positive or indeterminate QuantiFERON TB result may be re-tested once)
•If Quantiferon not available or providing indeterminate results after repeat testing : A tuberculin skin test reaction ≥10mm (≥5mm if receiving ≥15mg/d prednisone or its equivalent)
13. Relevant chronic or acute infections including human immunodeficiency virus (HIV) or viral hepatitis. A patient can be re-screened if the patient was treated and is cured from the acute infection.
14. Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma or squamous cell carcinoma of the skin, or history of cervical cancer in situ (treated >3years); patients with remote history of malignancy (<10 years prior) may be considered and have to be discussed with sponsor case-by-case
15. Major surgery (major according to the investigator’s assessment) performed within 12 weeks prior to randomization or planned during study conduct, e.g. hip replacement.
16. Pathological safety lab parameters: haemoglobin < 9 g/dL, total white blood count (WBC) < 3000 cells/μl, neutrophils < 1000 cells/μl, thrombocytes < 100.000/μl, creatinine ≥ 2 mg/dL, total bilirubin > 2 x ULN with ratio of direct/indirect >1 (patients with Gilbert’s syndrome are not excluded), Alkaline Phosphatase >3 x ULN. – measured and confirmed by Central laboratory at screening visit.
17. Currently enrolled in another investigational device or drug study.
18. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
19. Evidence of a current or previous disease, medical condition (including chronic alcohol or drug abuse) other than ulcerative colitis, surgical procedure, medical examination finding (including vital signs and electrocardiogram (ECG)), or laboratory value at the screening visit outside the reference range that in the opinion of the investigator is clinically significant and would make the study participant unreliable to adhere to the protocol or to complete the trial, compromise the safety of the patient, or compromise the quality of the data
20. Any psychiatric or social problems possibly interfering with ability to comply with all study visits/procedures
21. History of allergy/hypersensitivity to the systemically administered trial medication agent or its excipients. |
1. Signos de absceso abdominal durante la selección
2. Signos de colitis fulminante o megacolon tóxico durante la selección
3. Ileostomía, colostomía o estenosis sintomática del intestino ya solucionada
4. Tratamiento con:
•cualquier medicación no biológica (p.e. ciclosporina, tacrolimus, micofenolato de mofetilo, corticosteroides intravenosos, tofacitinib),
•cualquier tratamiento biológico con antagonistas de TNFα (adalimumab, infliximab, golimumab) o vedolizumab en las 8 semanas antes de la aleatorización
•5-ASA rectal, corticosteroides parenterales o rectales (icluyendo budesonida) en las 2 semanas antes del screening
• cualquier medicamento en investigación biológico para colitis ulcerosa (incluyendo etrolizumab: en las 8 semanas antes de la aleatorización)
•cualquier exposición previa a BI 655130, natalizumab o rituximab
5. Examen de heces positivos para C. difficile u otros patógenes intestinales <30 días antes del screening
6. Que se hayan sometido a cirugía previa o que se espera que puedan requerir intervención quirúrgica para colitis ulcerosa
7. Signos de displasia mucosa de colon moderada/grave o adenomas de colon, a no ser que se hayan extraido correctamente
8. Colangitis esclerosante primaria
9. Transplante fecal ≤ 6 meses antes del screening
10. Riesgo aumentado de complicaciones indfecciosas (p.e.infección pirogénica reciente, cualquier inmunodeficiencia congénita o adquirida (p.e.VIH), trasplante pasado de ógano o células madre)
11. Vacuna viva o atenuada en las 6 semanas anteriores al screening
12. Tuberculosis (TB) activa o latente: Pacientes con test de TB positivo a un mes del screening quedan excluidos:
•Resultado positivo QuantiFERON TB (Pacientes con resultados QuantiFERON TB indeterminados o sospecha de que sea un falso positivo pueden ser re-examinados una vez)
•Si Quantiferon no está disponible o da resultados indeterminados después de la repetición del test: un test de reacción en la piel (skin test reaction) a la tuberculina ≥10mm (≥5mm si se recibe ≥15mg/d de prednisona o su equivalente)
13. Infecciones crónicas o agudas relevantes incluyendo el virus de la inmunodeficiencia humana o la hepatitis vírica. Un paciente puede volver pasar por el screening si el paciente ya fue tratado y está curado de la infección aguda.
14.Cualquier malignidad activa o sepechada documentada o historial de malignidad el 5 años anteriores al screening , excepto carcinoma de células basales, carcinoma de celulas escamosas de la piel tratados apropiadamente, o historial de cámcer de cérvix in situ (tratado >3años); pacientes con historial remoto de malignidad (<10años) pueden considerarse y se deben decidir con el promotor caso por caso.
15. Cirugía mayor 8mayor según la evaluación del investigador) llevada a cabo en las 12 semanas antes de la aleatorización o planificada durante el desarrollo del ensayo, p.e.reemplazo cadera
16. Parámetros de laboratorio de seguridad patológicos hemoglobina < 9 g/dL, recuento leucocitário total 3000 células/μl, neutrófilos < 1000 células/μl, trombocitos <100.000 células/μl, creatinina ≥ 2 mg/dL, bilirubina total > 2 x ULN con ratio directo/indirecto >1 (pacientes con síndrome de Gilbert no están excluidos), fosfatasa alcalina >3 x ULN. - medido y confirmado por el laboratorio central en la vistita de screening.
17. Paciente actualmente participando en otro estudio con medicamento o producto en investigación
18. Mujeres embarazadas, en período de lactancia o que planeen quedarse embarazadas durante el ensayo
19. Signos de una enfermedad o condición médica (incluyendo abuso crónico de alcohol o drogas) actual o previa diferente a la colitis ulcerosa , procedimiento quirúrgico, hallazgo en el examen clínico (incluyendo signos vitales y electrocardiograma (ECG)), o valores de laboratorio en la visita de screening fuera del rango de referencia que en opionión del investigador sea clinicamente significativo y pudiera hacer que el participante en el estudio no se adheriera al protocolo o finalizara el ensayo, comprometiera la seguridad del paciente o comprometiera la calidad de los datos
20. Cualquier problema psiquiátrico o social que pueda interferir con la habilidad de cumplir con todas las vistas y procedimientos del estudio.
21. Historial de alergia/hipersensiblidad a la medicación del ensayo administrada sistémicamente o a sus excipientes. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Part 1 and Part 2: Proportion of patients with Clinical Remission at week 12 (defined as mMCS SFS=0 or 1, if drop ≥1 from BL; and RBS=0; and mESS≤1) |
| 1. Parte1 y Parte2: Proporción de pacientes en Remisión Clínica en la semana 12 ((definido como SFS (frecuencia de deposiciones, [stool frequency subscore]) de mMCS = 0 o 1, si disminuye ≥ 1 respecto al inicio; y RBS (hemorragia rectal, [rectal bleeding subscore]) = 0; y mESS ≤ 1) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Part 2/Phase III only: Proportion of patients with Mucosal Healing at week 12 (defined as mESS ≤ 1)
2. Part 2/Phase III only: Change in IBDQ score from baseline at week 12
3. Part 1 and Part 2: Proportion of patients with combined Mucosal healing and histologic remission at week 12 (defined as mESS ≤ 1 and Robarts Histology Index ≤ 6)
4. Part 2/Phase II only: Proportion of patients with Mucosal Healing at week 12
5. Part 2/Phase II only: Proportion of patients with Clinical response at week 12 |
1. Sólo Parte 2/Fase III: Porcentaje de pacientes con Cicatrización de la Mucosa a la semana 12 (definido como la subpuntuación endoscópica modificada [mESS] ≤ 1).
2. Sólo Parte 2/Fase III: Cambio en la puntucaión IBDQ respecto al inicio en la semana 12
3. Parte 1 y Parte 2: Porcentaje de pacientes con cicatrización de la mucosa y remisión histológica combinados en la semana 12 (definido como mESS ≤ 1 e índice histológico de Robarts ≤ 6)
4. Sólo Parte 2/Fase II: Porcentaje de pacientes con Cicatrización de la Mucosa a la semana 12
5. Sólo Parte 2/Fase II: Porcentaje de pacientes con respuesta clínica en la semana 12 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 12
2. Week 0 and Week 12
3. Week 12
4. Week 12
5. Week 12 |
1. Semana 12
2. Semana 0 y semana 12
3. Semana 12
4. Semana 12
5. Semana 12 |
|
| 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 | No |
| 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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarkers associated with Ulcerative Colitis and the IL-36R pathway |
| Biomarcadores asociados a Colitis Ulcerosa y la via de senyaliación IL-36R |
|
| 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) | Yes |
| 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 | 4 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| 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
|
| LVLS |
| Última visita del último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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