| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Crohn's Disease |
| Enfermedad de Crohn |
|
| E.1.1.1 | Medical condition in easily understood language |
| Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract that causes significant morbidity, impact on quality of life, and health care expenditures. |
| La Enfermedad de crohn es una enfermedad inflamatoria crónica del tracto intestinaal causante de una morbilidad significativa, impacto en la calidad de vida y gastos de atencion medica |
|
| 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 | 10011401 |
| E.1.2 | Term | Crohn's disease |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011398 |
| E.1.2 | Term | Crohn's |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal 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 |
| • Objective: To assess the effect of BMS-986165 on clinical remission and endoscopic response at the end of the Induction Period |
| • Objetivo: evaluar el efecto de BMS-986165 sobre la remisión clínica y la respuesta endoscópica al final del período de inducción |
|
| E.2.2 | Secondary objectives of the trial |
• Objective: To assess the effect of BMS-986165 on endoscopic remission at Week 12 (Day 85)
• Objective: To assess the effect of BMS-986165 on clinical response at end of the Induction Period (Week 12 [Day 85])
• Objective: To assess the effect of BMS-986165 on clinical response through end of the Maintenance Period (Week 52 [Day 365])
• Objective: To assess the effect of BMS-986165 on clinical remission through the end of the Maintenance Period (Week 52 [Day 365])
• Objective: To endoscopically assess the effect of BMS-986165 on gut mucosal disease activity
• Objective: To assess the effect of BMS-986165 on deep remission |
• Evaluar el efecto de BMS-986165 sobre la remisión endoscópica en la semana 12 (día 85).
• Evaluar el efecto de BMS-986165 sobre la respuesta clínica al final del período de inducción (semana 12 [día 85]).
• Evaluar el efecto de BMS-986165 sobre la respuesta clínica hasta el final del período de mantenimiento (semana 52 [día 365]).
• Evaluar el efecto de BMS-986165 sobre la remisión clínica hasta el final del período de mantenimiento (semana 52 [día 365]).
• Evaluar mediante endoscopia el efecto de BMS-986165 sobre la actividad de la enfermedad a nivel de la mucosa intestinal.
• Evaluar el efecto de BMS-986165 sobre la remisión profunda. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)Signed Written Informed Consent
a)Willing to participate in the study and sign the ICF
b)Willing and able to complete all study-specific procedures and visits
2)Type of Subject and Target Disease Characteristics
a)Documented diagnosis of CD of at least 3 months’ duration,with colitis,ileitis, or ileocolitis,confirmed by:
•Source:Medical records with report of an ileocolonoscopy(full colonoscopy with the intubation of terminal ileum)which shows features consistent with CD,as determined by the procedure performing physician,AND
•Source:Medical record documentation of a histopathology report showing features consistent with CD,as determined by the local pathologist
Note:If no previous confirmation of diagnosis is available or if previous diagnosis is not deemed conclusive,at time of baseline endoscopy,histology must be performed and read locally to confirm diagnosis of CD before proceeding to randomization
b)Must have active moderate to severe CD,as defined by:
•CDAI score of 220 to 450 AND
•PRO 2:Average daily score for abdominal pain ≥2 OR average daily number of very soft(loose)or liquid (watery)stools(BSS Type 6 or 7 only)≥ 4,as collected in a 7-day diary,AND
•Evidence of active inflammation in at least 1 of the 5 ileocolonic segments(based on central reading) with total SES-CD≥6 or SES-CD≥4 if only isolated ileitis is present on baseline endoscopy
c)Must have had an inadequate response, loss of response, or intolerance to a standard treatment course of 1 or more of the following standard of care medications as below:
•Oral aminosalicylates(eg,mesalamine,sulfasalazine,olsalazine,balsalazine)at or above the approved label dose for induction therapy for at least 6 weeks prior to randomization
•Oral CS:Prednisone 20mg/day or equivalent for at least 2 weeks,and/or 2 failed attempts to taper oral CS below prednisone or equivalent 10mg daily
•IV Corticosteroids: hydrocortisone≥400mg/day or equivalent for at least 1 week,
•Immunomodulators (AZA≥2mg/kg/day,6-MP≥1mg/kg/day,MTX≥25mg/week,or documentation of a therapeutic concentration of 6 thioguanine nucleotide) for at least 12 weeks,or
•Biologics(eg,infliximab,adalimumab,certolizumab pegol,vedolizumab,natalizumab)Subjects can be included if treatment with a biologic was stopped due to primary(eg,did not respond initially after treatment for at least 12 weeks at the approved dose)or secondary nonresponse(responded initially but then lost response with continued therapy)or were intolerant to treatment.
d)This study permits the rescreening of a subject that has been deemed as ineligible(screen failure) during the Screening Period(ie,subject has not been randomized/has not been treated; ection 6.5)If re enrolled,the subject must be re-consented(ie,re-signing of the ICF)and rescreened(if outside the 28-day Screening Period window)Only 1 re enrollment per subject is permissible
3)Age and Reproductive Status
a)Men and women subjects,aged 18 to 75 years inclusive at the time of screening
b)Women of childbearing potential(WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25IU/L or equivalent units of beta-human chorionic gonadotropin)within 24 h prior to the start of study treatment,unless they are surgically sterile had a hysterectomy,or have been postmenopausal for at least 1 year(12 consecutive months without menses)In case of doubt,a determination of serum follicle-stimulating hormone(FSH)can be performed with FSH levels>35mIU/mL confirming menopause status.
c)Women must not be breastfeeding
d)WOCBP must agree to follow instructions for method(s)of contraception for the duration of treatment with study treatment(s)BMS 986165(36 weeks)plus 5 half-lives of study treatment BMS986165(3 days)plus 30 days(duration of ovulatory cycle)for a total of 33 days post treatment completion
e)WOCBP who are not heterosexually active are exempt from contraceptive requirements,and still must undergo pregnancy testing as described in this section
f)Investigators shall counsel WOCBP and men on the importance of pregnancy prevention and the implications of an unexpected pregnancy.Investigators shall advise on the use of highly effective methods of contraception,which have a failure rate of<1% when used consistently and correctly
g)Men who are sexually active with WOCBP must agree to follow instructions for method(s)of contraception for the duration of treatment with study treatment(s)plus 5 half-lives of the study treatment(3 days)after the final dose of study treatment
h)Azoospermic males are exempt from contraceptive requirements.WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements,and still must undergo pregnancy testing as described in this section
i)Male subjects must be willing to refrain from sperm donation during the entire duration of treatment plus 5 half-lives of study treatment(3 days)after the final dose of study treatment |
1)Consentim informado por escrito y firmado
a)Disposición a participar en estudio y firmar CI
b)Disposición y capacidad para realizar todas las visitas y procedim espec de estudio
2)Tipo de pte y caract de enfermedad objeto de estudio
a)Diagnóstico documentado de EC de al menos 3 meses de duración,con colitis,ileitis o ileocolitis,confirmado por:
•Documento original:historia clínica con informe de ileocolonoscopia(colonoscopia completa con intubación del íleon terminal),que muestre caract compatibles con EC determinadas por el médico que realizó el procedim Y
•Documento original:documentación en historia clínica de informe histopatológico que muestre caract compatibles con EC determinadas por anatomopatólogo local
Nota:Si no dispone de confirmación previa de diag,o no se considera concluyente un diag previo,en el momento de endoscopia inicial se deberá realizar,e interpretar localmente,estudio histológico para confirmar diag de EC antes de aleatorización
b)Presentar EC activa de moderada a grave,definida por:
•puntuación CDAI 220-450,Y
•RCP 2:Puntuación diaria promedio de dolor abdominal≥2,O BIEN frecuencia diaria promedio de heces muy blandas(sueltas)o líquidas(acuosas)(BSS 6 o 7 solamente)≥4,según registro en diario de 7 días,Y
•Indicios e inflamación activa en al menos 1 de los 5 segmentos ileocolónicos(según interpretación central)con SES-CD≥6,o SES-CD≥4 si en la endoscopia inicial solo se halla presente ileitis aislada
c)Debe haber presentado respuesta inadecuada,pérdida de respuesta o intolerancia a ciclo de tto de referencia con 1 o más de los siguientes medicam del tto de referencia como sigue:
•aminosalicilatos orales(ej:mesalamina,sulfasalazina,olsalazina,balsalazina)a dosis de ficha téc aprobada para tto de inducción,o dosis superior,durante al menos 6 sem antes de aleatorización
•CS oral:prednisona 20mg/día o equiv durante al menos 2 sem;y/o 2 intentos fallidos para disminuir el CS oral por debajo de prednisona o equivalente 10mg/dia
•Conrticoides IV:hidrocortisona IV≥400mg/día o equiv durante al menos 1 sem;
•inmunomoduladores(AZA≥2mg/kg/día,6-MP≥1mg/kg/día,MTX≥25mg/sem,o concentración terapéutica documentada de nucleótido de 6-tioguanina)durante al menos 12 sem;o
•medicam biológicos(ej:infliximab,adalimumab,certolizumab pegol,vedolizumab, natalizumab)Se podrá incluir a ptes cuyo tto con un medicam biológico se haya interrumpido debido a falta de respuesta primaria(ej:no responden inicialmente tras tto durante al menos 12 sem a dosis autorizada)o secundaria(que respondieran inicialmente pero después perdieran la respuesta con tto continuado)o que hayan presentado intolerancia al tto.
d)En este estudio se permite volver a someter a selecc a un pte considerado no apto(error de selecc)durante la selecc(esto es,pte no aleatorizado/no tratado;sección 6.5)Si vuelve a ser incluido,el pte deberá prestar de nuevo CIvy ser sometido de nuevo a selecc(si ha finalizado el intervalo de 28 días de la fase de selecc).Solo se permite una nueva inclusion por pte.
3)Edad y estado reproductivo
a Hombres y mujeres entre 18 y 75 años en el momento de la selecc
b)Las mujeres potencialmente fértiles(MPF)deberán hacerse prueba de embarazo en orina o suero negativa(sensibilidad mínima,25UI/l o unidades equiv de gonadotropina coriónica humana-beta)en 24 h anteriores al inicio del tto de estudio,salvo que sean quirúrgicamente estériles,se hayan sometido a histerectomía o hayan sido postmenopáusicas durante al menos 1 año(12 meses consecutivos sin menstruaciones)En caso de duda se podrá llevar a cabo determinación FSH para confirmar estado menopáusico con niveles de FSH>35mUI/ml
c)Las mujeres no podrán estar amamantando
d)Las MPF deben estar conformes en seguir instrucc relativas a métodos anticonceptivos mientras reciban el/los tto(s)de estudio BMS986165(36 sem)más 5 semividas de tto de estudio BMS986165(3 días)y 30 días(duración del ciclo ovulatorio):total de 33 días tras conclusión de estudio
e)Las MPF que no sean activas heterosexualmente están exentas de cumplir requisitos relativos a métodos anticonceptivos,ademas deben someterse a pruebas de embarazo explicadas en esta secc
h)Los investigadores asesorarán a MPF y hombres sobre la importancia de evitar embarazo e implicaciones de embarazo no planificado.Los investigadores facilitarán asesoramiento sobre uso de métodos anticonceptivos de alta eficacia,con tasa de error <1%cuando se utilizan de forma sistemática y correcta
g)Los hombres sexualmente activos con MPF deben aceptar seguir instrucciones para el(los)métodos anticonceptivos durante el tto con BMS-986165 o placebo más 5 semividas de estudio de tto(3 días)después de dosis final de tto de estudio
g)Los hombres azoospérmicos están exentos de cumplir requisitos anticonceptivos
f)Los sujetos varones deben estar dispuestos a abstenerse de la donación de esperma durante toda la duración del tto más 5 semividas del tto de estudio(3 días)después de la última dosis del tto de estudio |
|
| E.4 | Principal exclusion criteria |
1) Target Population
a) Severe or fulminant colitis that is likely to require surgery or hospitalization
b) Presence of a diagnosis of alternative forms of colitis (infectious, inflammatory including ulcerative colitis, malignant, toxic, indeterminate, etc.) other than CD
c) Presence of a stoma, gastric or ileoanal pouch, previous proctocolectomy or total colectomy, symptomatic obstructive disease such as stenosis or obstructive strictures, abscess or suspected abscess, pouchitis, short bowel syndrome, or history of bowel perforation
d) History of intra-abdominal abscess within the last 60 days
• Previous intra-abdominal abscess that has been drained and successfully treated with a local standard course of antimicrobial therapy is permitted (The course must have completed at least 60 days prior to Day 1)
e)History of diverticulitis within the last 60 days
• Previous diverticulitis that has been successfully treated with a local standard course of antimicrobial therapy is permitted. (The course must have completed at least 60 days prior to Day 1)
f) Receiving tube feeding, defined formula diets, or total parenteral alimentation
g) Current colonic dysplasia or past colonic dysplasia that has not been definitively treated
h) History of infectious (bacterial, viral, fungal, parasitic, etc.) colitis within past 30 days; must be fully treated to rescreen
i) Use of therapeutic enema or suppository, other than required for ileocolonoscopy, within 7 days prior to screening or during the Screening Period
j) Prior treatment with specific lymphocyte-depleting agents, such as alemtuzumab, rituximab, and other agents such as ustekinumab, are prohibited within 12 months prior to the first dose of study treatment during the Induction Period. Please note that lack of response to ustekinumab (as well as other anti-12/23 p40 antibodies) or anti-IL-23 p19 antibodies is criteria for exclusion (also see exclusion criterion 3.b).
k) Receipt of either lymphocyte apheresis or selective monocyte, granulocyte apheresis (eg, Cellsobra®) is prohibited within 12 months prior to the first dose of study treatment during the Induction Period
l) Previous exposure to BMS-986165 in any study
m) Previous stem cell transplantation
n) Previous treatment with investigational agents within 12 weeks or 5 half-lives (whichever is longer) prior to the first dose of study treatment during the Induction Period |
1) Población del estudio
a) Colitis grave o fulminante que probablemente requiera cirugía u hospitalización
b) Existencia de un diagnóstico de formas alternativas de colitis (colitis infecciosa o inflamatoria, incluidas las colitis ulcerosas, malignas, tóxicas, indeterminadas, etc.) distintas de la EC
c) Presencia de un estoma, bolsa gástrica o ileoanal, proctocolectomía o colectomía total previa, enfermedades obstructivas tales como estenosis o estenosis obstructivas sintomáticas, absceso o sospecha de absceso, bolsitis, síndrome de intestino corto o historial de perforación intestinal
d) Historial de absceso intraabdominal en los últimos 60 días
• Se permite el absceso intraabdominal previo drenado y tratado con éxito con un ciclo del tratamiento antimicrobiano local de referencia (el ciclo debe haber finalizado al menos 60 días antes del día 1)
e) Historial de diverticulitis en los últimos 60 días
• Se permite la diverticulitis previa tratada con éxito con un ciclo del tratamiento antimicrobiano local de referencia. (El ciclo debe haber finalizado al menos 60 días antes del día 1)
f) Recibir alimentación por sonda, dietas de fórmula definida o alimentación parenteral total
g) Displasia de colon actual o pasada que no haya sido tratada definitivamente
h) Historial de colitis infecciosa (bacteriana, vírica, fúngica, parasitaria, etc.) en los últimos 30 días; para repetir la selección debe ser tratada por completo.
i) Uso de un enema o supositorio, distintos de los requeridos para la ileocolonoscopia, en los 7 días previos a la selección o durante esa fase.
j) Está prohibido el tratamiento previo con agentes específicos reductores de linfocitos, como alemtuzumab, rituximab, y otros agentes como ustekinumab, en los 12 meses anteriores a la primera dosis del tratamiento del estudio durante el período de inducción. Debe tenerse en cuenta que la falta de respuesta a ustekinumab (y a otros anticuerpos anti-p40 de IL-12/IL-23) o a anticuerpos anti-p19 de IL-23 constituye un criterio de exclusión (ver también criterio de exclusión 3.b).
k) Está prohibido recibir aféresis de linfocitos o aféresis selectiva de monocitos y granulocitos (p. ej., Cellsobra®) en los 12 meses anteriores a la primera dosis del tratamiento del estudio durante el período de inducción
i) Exposición previa a BMS-986165 en cualquier estudio
m) Trasplante previo de células madre
n) Tratamiento previo con agentes en fase de investigación en el período de 12 semanas o (si constituye un período más largo) de 5 semividas anterior a la primera dosis del tratamiento del estudio durante el período de inducción |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-primary endpoints:
Proportion of subjects achieving clinical remission at Week 12 (Day 85)
Proportion of subjects achieving endoscopic response at Week 12 (Day 85) |
o Proporción de pacientes que logran la remisión clínica en la semana 12 (día 85).
o Proporción de pacientes que logran la respuesta endoscópica en la semana 12 (día 85). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
o Endpoint: Proportion of subjects who achieve endoscopic remission at Week 12 (Day 85)
o Endpoint: Proportion of subjects who achieve a clinical response at Week 12 (Day 85)
o Endpoint: Proportion of subjects who achieve a clinical response through Week 52 (Day 365)
o Endpoint: Proportion of subjects achieving clinical remission at Week 52 (Day 365)
o Endpoints:
Proportion of subjects achieving endoscopic remission at Week 52 (Day 365)
Proportion of subjects who achieve an endoscopic response at Week 52 (Day 365)
Proportion of subjects achieving complete mucosal healing at Weeks 12 and 52
Change from baseline in SES-CD at Weeks 12 and 52
o Endpoints:
Proportion of subjects achieving deep remission at Week 12 (Day 85)
Proportion of subjects maintaining deep remission at Week 52 (Day 365) |
o Criterio de valoración: Proporción de pacientes que alcanzan la remisión endoscópica en la semana 12 (día 85)
o Criterio de valoración: Proporción de pacientes que alcanzan una respuesta clínica en la semana 12 (día 85)
o Criterio de valoración: Proporción de pacientes que alcanzan una respuesta clínica hasta la semana 52 (día 365)
o Criterio de valoración: Proporción de pacientes que alcanzan la remisión clínica en la semana 52 (día 365)
o Criterios de valoración:
Proporción de pacientes que alcanzan la remisión endoscópica en la semana 52 (día 365)
Proporción de pacientes que alcanzan una respuesta endoscópica en la semana 52 (día 365)
Proporción de pacientes que consiguen una cicatrización completa de la mucosa en las semanas 12 y 52
Cambio con respecto al inicio en el SES-CD en las semanas 12 y 52
o Criterios de valoración:
Proporción de pacientes que alcanzan una remisión profunda en la semana 12 (día 85)
Proporción de pacientes que mantienen la remisión profunda en la semana 52 (día 365) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12 and 52 weeks |
| semanas 12 y 52 |
|
| 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 | 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 | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Mexico |
| Poland |
| Romania |
| 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 |
| Ultima visita del ultimo paciente |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 2 |
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