| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe Active Ulcerative Colitis |
| colitis ulcerosa (CU) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ulcerative Colitis |
| colitis ulcerosa |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| 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 effect of efavaleukin alfa on induction of clinical remission |
| Evaluar el efecto de efavaleucina alfa en la inducción de la remisión clínica. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of efavaleukin alfa on induction of clinical response
- To evaluate the effect of efavaleukin alfa as induction therapy on endoscopic remission
- To evaluate the effect of efavaleukin alfa as induction therapy on mucosal healing
- To evaluate the effect of efavaleukin alfa as induction therapy on change in histological score
- To evaluate the safety and tolerability of efavaleukin alfa |
-Evaluar el efecto de efavaleucina alfa en
la inducción de la respuesta clínica.
-Evaluar el efecto de efavaleucina alfa en la inducción de la remisión endoscópica.
-Evaluar el efecto de efavaleucina alfa en
la inducción de la remisión sintomática.
-Evaluar el efecto de efavaleucina alfa
como tratamiento de inducción en la
cicatrización de la mucosa.
-Evaluar el efecto de efavaleucina alfa
como tratamiento de inducción en el
cambio de la puntuación histológica. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
101 Subject has provided informed consent prior to initiation of study .
102 Aged from 18 years to 80 years at screening visit, except in South Korea where from age 19 years to 80 years at screening visit; and in Taiwan where age from 20 years to 80 years at screening visit.
103 Diagnosis of UC established at least 3 months prior to enrollment by clinical and endoscopic evidence and corroborated by a histopathology report.
104 Moderately to severely active UC as defined by a modified Mayo score of 5 to 9, with a centrally read rectosigmoidoscopy endoscopic subscore at least 2 and no subscore less than 1 prior to day 1.
105 Has documentation of
A surveillance colonoscopy within 12 months of day 1 visit for subjects with pancolitis of at least 8 years duration, or subjects with left-sided colitis of over 12 years duration, or subjects with
primary sclerosing cholangitis.
For all other subjects, up-to-date colorectal cancer surveillance
(performed according to local standard). Subjects who do not have a
colonoscopy report available in source documentation will have a
colonoscopy instead of rectosigmoidoscopy performed as the screening endoscopy for the study, at the discretion of the investigator.
106 Subjects must have demonstrated inadequate response, loss of response, or intolerance to at least 1 conventional therapy, biologic therapy, or targeted small molecule therapy (ie, JAK-inhibitor).
Conventional therapy failed subjects:
- Corticosteroids (corticosteroid-refractory colitis, defined as signs
and/or symptoms of active UC despite oral prednisone (or equivalent)
at doses of at least 30 mg/day for a minimum of 2 weeks; or
corticosteroid-dependent colitis, defined as: an inability to reduce
corticosteroids below the equivalent of prednisone 10 mg/day within
3 months of starting corticosteroids without a return of signs and/or
symptoms of active UC; or a relapse within 3 months of completing a
course of corticosteroids
- History of intolerance of corticosteroids (including, but not limited to,
Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, or
neuropsychiatric side-effects, including insomnia, associated with
corticosteroid treatment)
- Immunomodulators: signs and/or symptoms of persistently active
disease despite at least 3 months treatment with one of the following
at locally approved doses: oral azathioprine or 6-mercaptopurine, or oral azathioprine or 6-mercatopurine within a therapeutic range as judged by thioguanine metabolite testing, or a combination of a thiopurine and allopurinol within a therapeutic range as judged by thioguanine metabolite testing
- History of intolerance to at least 1 immunomodulator (including but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, and lymphopenia) and have neither failed nor demonstrated an intolerance to a biological medication (anti-TNF
antibody, anti-integrin antibody, or IL-12/23 antagonists) that is
indicated for the treatment of UC
Biologic or targeted small molecule therapy failed subjects: those who
demonstrated inadequate response or loss of response or intolerance to biologic therapy for UC (eg, anti-TNF antibodies or IL-12/23 antagonists, anti-integrin antibodies) or targeted small molecules (eg, JAK inhibitors).
The therapy used to qualify the subject for entry into this category must be approved for the treatment of UC in the country of use, at the time of use. Subjects must fulfil one of the following criteria:
Inadequate response: signs and symptoms of persistently active
disease despite induction treatment at the approved induction dosing
that was indicated in the product label at the time of use
Loss of response: recurrence of signs and symptoms of active
disease during approved maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not quality as
having failed or being intolerant to UC biological therapy or JAK
inhibitor)
Intolerance: history of intolerance to infliximab, adalimumab,
golimumab, vedolizumab, ustekinumab, tofacitinib or other approved
biologicals or JAK inhibitors (including but not limited to
infusion-related event, demyelination, congestive heart failure, or any
other drug-related adverse event that led to a reduction in dose or
discontinuation of the medication)
107 If receiving any of the following therapies, subjects must have stable dosage for the specified duration:
5-aminosalicylates (ASAs), stable dosage for at least 2 weeks prior to screening endoscopy
Oral corticosteroids: prednisone up to 20 mg/day or its equivalent, stable dose for 2 weeks prior to screening endoscopy
Budesonide: extended release tablets 9 mg/day [budensonide MMX], stable dose for at least 2 weeks prior to screening endoscopy
Conventional immunomodulators: azathioprine, 6-mercaptopurine,
methotrexate, stable dosage for at least 8 weeks prior to screening endoscopy |
Los sujetos son elegibles para ser incluidos en el estudio solo si cumplen todos los
criterios siguientes:
101 El sujeto ha proporcionado su consentimiento informado antes de iniciar
cualquier procedimiento o actividad específico del estudio. En Japón, si un
sujeto es menor de 20 años en el momento de firmar el consentimiento
informado, se debe obtener el consentimiento informado tanto del sujeto como
de su representante legal.
102 Edad comprendida entre ≥ 18 y < 80 años en la visita de selección, excepto en
Corea del Sur, donde la edad oscila entre ≥ 19 y < 80 años en la visita de
selección, y en Taiwán, donde la edad oscila entre ≥ 20 y < 80 años en la
visita de selección.
103 Diagnóstico de CU establecido ≥ 3 meses antes de la inclusión mediante
evidencia clínica y endoscópica y corroborado por un informe histopatológico.
Si no se dispone de un informe histopatológico en el momento de la selección,
se pueden realizar biopsias adicionales durante el período de selección para
corroborarlo mediante un análisis histopatológico local.
104 CU activa de moderada a grave, definida por una puntuación de Mayo
modificada de 5 a 9, con una subpuntuación endoscópica mediante una
rectosigmoidoscopia de lectura centralizada de ≥ 2 y sin una subpuntuación de
< 1 antes del día 1.
105 Poseer documentación de
• Una colonoscopia de vigilancia (realizada de acuerdo con el tratamiento
estándar local) en los 12 meses posteriores a la visita del día 1 para los
sujetos con pancolitis de > 8 años de duración, para los sujetos con colitis
en el lado izquierdo de > 12 años de duración o para los sujetos con
colangitis esclerosante primaria.
• En todos los demás sujetos, vigilancia actualizada del cáncer colorrectal
(realizada de acuerdo con el tratamiento estándar local). A los sujetos que
no dispongan de un informe de colonoscopia en la documentación original
se les realizará una colonoscopia en lugar de una rectosigmoidoscopia
como endoscopia de selección en el estudio, según el criterio del
investigador.
106 Los sujetos deben haber demostrado una respuesta inadecuada, pérdida de
respuesta o intolerancia a al menos 1 tratamiento convencional, tratamiento
biológico o tratamiento dirigido con fármacos de molécula pequeña (es decir,
un inhibidor de la JAK).
Ver protocolo para resto de criterios de inclusión |
|
| E.4 | Principal exclusion criteria |
201 Diagnosis of Crohn’s disease, inflammatory bowel disease-unclassified, microscopic colitis, ischemic colitis, or clinical findings suggestive of Crohn’s disease.
202 Disease limited to the rectum.
203 Evidence of toxic megacolon, fulminant colitis, intra-abdominal abscess, or stricture/stenosis within the small bowel or colon.
204 Previous bowel resection or intestinal or intra-abdominal surgery.
Have had extensive surgery for UC, or are likely to require surgery for the treatment of UC during the study. Subjects who have had limited surgery for UC may be allowed in the study, if this does not affect the assessment of efficacy. Discussion with the sponsor must occur prior to screening of such subjects.
Have had any small bowel or colonic surgery within 6 months of day 1.
Have had any nonintestinal intra-abdominal surgery within 3 months of day 1.
205 Adenoma and dysplasia exclusion criteria:
Any current sporadic adenoma without dysplasia that has not been removed. Once completely removed, the subject is eligible for study.
Dysplasia occurring in flat mucosa, sporadic adenomas containing dysplasia, and dysplasia-associated lesions or masses will be managed as follows:
Any history or current evidence of high-grade dysplasia.
Any history or current evidence of dysplasia occurring in flat mucosa.
This includes histopathology reporting indefinite for dysplasia, low-grade dysplasia, and high-grade dysplasia.
Any history or current evidence of a nonadenoma-like
dysplasia-associated lesions or masses, with or without evidence of
dysplasia.
Any current sporadic adenoma containing dysplasia or any current
adenoma-like dysplasia-associated lesions or masses that has not been
removed. Once completely removed, the patient is eligible for the study.
206 Stool positive for Clostridium difficile toxin at screening and other enteric pathogens including but not limited to ova, parasites, Campylobacter, salmonella, shigella, E coli 0157:H7, and Yersinia enterocolitica.
207 History or evidence of suicidal ideation (severity of 4 or 5) or any suicidal behavior based on an assessment with the Columbia Suicide Severity Rating Scale (C-SSRS) at screening
208 Active infection for which anti-infectives were indicated within 4 weeks prior to screening visit OR presence of serious infection, defined as requiring hospitalization or intravenous anti-infectives within 8 weeks prior to screening visit.
209 Active tuberculosis or latent tuberculosis with no documented past history of adequate treatment per local standard of care.
210 Positive test for TB during screening defined as: either a positive or indeterminate QuantiFERON-TB or T-spot test OR positive purified protein derivative. Subjects with a positive PPD and a history of Bacillus Calmette-Guerin vaccination are allowed to enroll with a negative QuantiFERON®-TB or T-Spot test and negative chest X-ray.
Indeterminate QuantiFERON®-TB or T-spot test can be repeated once,
based on investigator judgment. Subjects can enroll if second result is
negative. Subjects with persistent indeterminate or positive test results must proceed as below.
Subjects with a positive PPD test or a positive or indeterminate QuantiFERON®-TB or T-Spot test are allowed to enroll if they meet ALL the following criteria at screening:
No symptoms per tuberculosis worksheet provided by Amgen
documented history of adequate TB treatment or prophylactic treatment for latent TB
No known exposure to a case of active tuberculosis after most recent
treatment/prophylaxis
Chest X-ray with no new radiographic findings suggestive of active TB
211 Any history of malignancy
212 Presence of 1 or more significant concurrent medical conditions per the investigator judgement
213 Positive for hepatitis B surface antigen (HBsAg); or positive for hepatitis B core antibody or hepatitis B surface antibody in the presence of detectable viral DNA in peripheral blood, assessed by polymerase chain reaction. Subjects positive for HBcAb and/or HBsAb without history of prior vaccination and without detectable viral DNA by PCR are allowed to enroll, provided the subject undergoes monitoring of viral DNA by PCR at every
2 months during the treatment period and up to 6 weeks after the end of treatment for the study. Patients with a history of hepatitis B vaccination without history of hepatitis B infection are allowed to enroll.
214 Positive for hepatitis C antibody in the presence of detectable viral RNA in peripheral blood, assessed by PCR. Subjects positive for HCAb without detectable viral RNA by PCR are allowed to enroll.
215 Known history of Human Immunodeficiency Virus (HIV) or positive HIV test at screening.
216 Inherited immunodeficiency syndrome.
217 Required systemic corticosteroid use for any indication other than UC.
218 Have had a bone marrow or solid organ transplantation.
219 Have had extra-abdominal surgery without full recovery prior to screening. |
Relacionados con la enfermedad
201 Diagnóstico de enfermedad de Crohn, enfermedad inflamatoria intestinal no
clasificada (colitis indeterminada), colitis microscópica, colitis isquémica o
hallazgos clínicos indicativos de enfermedad de Crohn.
202 Enfermedad limitada al recto (es decir, a menos de 10 cm del borde anal).
203 Evidencia de megacolon tóxico, colitis fulminante, absceso intraabdominal o
estenosis/estrechez dentro del intestino delgado o del colon.
204 Resección intestinal previa o cirugía intestinal o intraabdominal.
• Haberse sometido a una cirugía extensa para la CU (por ejemplo,
colectomía subtotal), o es probable que requieran cirugía para el
tratamiento de la CU durante el estudio. Los sujetos que se hayan sometido
a una cirugía limitada para la CU (por ejemplo, resección segmentaria de
colon) podrán participar en el estudio, si esto no afecta a la evaluación de
la eficacia. Se debe hablar con el promotor antes de la selección de dichos
sujetos.
• Haberse sometido a una cirugía de intestino delgado o de colon en los
6 meses posteriores al día 1.
• Haberse sometido a una cirugía intraabdominal no intestinal en los
3 meses posteriores al día 1.
205 Criterios de exclusión relativos a adenomas y displasias:
• Cualquier adenoma esporádico actual sin displasia (pólipos adenomatosos
que se produzcan cerca de las zonas conocidas de colitis) que no se haya
extirpado. Una vez extirpado por completo, el sujeto es elegible para el
estudio.
• La displasia que se produce en la mucosa plana, los adenomas
esporádicos que contienen displasia y las lesiones o masas asociadas a la
displasia se tratarán de la manera siguiente:
− Cualquier antecedente o evidencia actual de displasia de alto grado.
− Cualquier antecedente o evidencia actual de displasia en la mucosa
plana. Esto incluye una histopatología que considere como indefinidas
la displasia, la displasia de bajo grado y la displasia de alto grado.
− Cualquier antecedente o evidencia actual de lesiones o masas
asociadas a displasias distintas de las del adenoma, con o sin evidencia
de displasia.
− Cualquier adenoma esporádico actual que contenga displasia o
cualquier lesión o masa asociada a displasia actual similar a la del
adenoma que no se haya extirpado. Una vez extirpado por completo, el
paciente es elegible para el estudio.
206 Heces positivas para la toxina Clostridium difficile en el momento de la
selección y otros patógenos entéricos, como óvulos, parásitos, Campylobacter,
Salmonella, Shigella, E. coli 0157:H7 y Yersinia enterocolitica.
207 Antecedentes o evidencia de ideación suicida (gravedad de 4 o 5) o cualquier
comportamiento suicida basado en una evaluación con la escala Columbia para
evaluar el riesgo de suicidio (C-SSRS) en el momento de la selección.
Para resto de criterios de exclusión ver protocolo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Clinical remission at week 12 |
| Remisión clínica en la semana 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Clinical response at week 12
Endoscopic remission at week 12
Symptomatic remission at week 12
Combined endoscopic remission and histologic remission of the colon tissue at week 12
Change from baseline in histological score at week 12 as measured by Geboes score
Treatment-emergent adverse events |
-Respuesta clínica en la semana 12.
-Remisión endoscópica en la
semana 12.
-Remisión sintomática en la semana 12.
-Combinación de remisión
endoscópica y remisión
histológica del tejido del colon en
la semana 12.
-Cambio respecto al valor basal
en la puntuación histológica en la
semana 12 según la puntuación
de Geboes.
-Acontecimientos adversos
aparecidos durante el
tratamiento. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Canada |
| Japan |
| Korea, Democratic People's Republic of |
| Mexico |
| Russian Federation |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
| Austria |
| Belgium |
| Bulgaria |
| Czechia |
| Denmark |
| Finland |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Spain |
| Switzerland |
|
| 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
|
| End of long-term treatment (Long-term extension is additional 40 week +6 week follow-up) |
| Fin del tratamiento a largo plazo (la extensión a largo plazo es un seguimiento adicional de 40 semanas + 6 semanas) |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 7 |
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