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    EudraCT Number:2018-003986-33
    Sponsor's Protocol Code Number:APD334-302
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-02-24
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2018-003986-33
    A.3Full title of the trial
    A Phase 3, Randomized, Double Blind, Placebo Controlled, 12 Week Study to Assess the Efficacy and Safety of Etrasimod in Subjects with Moderately to Severely Active Ulcerative Colitis
    Estudio en fase III, aleatorizado, doble ciego, controlado con placebo, de 12 semanas de duración para evaluar la eficacia y la seguridad de etrasimod en sujetos con colitis ulcerosa activa de moderada a grave
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study evaluating the efficacy and safety of Etrasimod in the treatment of patients with moderately to severely active Ulcerative Colitis
    Estudio para evaluar la eficacia y la seguridad de etrasimod en sujetos con colitis ulcerosa activa de moderada a grave
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberAPD334-302
    A.5.4Other Identifiers
    Name:IND numberNumber:125154
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorArena Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportArena Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationArena Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointGiles Hulley
    B.5.3 Address:
    B.5.3.1Street Address6154 Nancy Ridge Drive
    B.5.3.2Town/ citySan Diego - CA
    B.5.3.3Post code92121
    B.5.3.4CountryUnited States
    B.5.4Telephone number034912071350
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEtrasimod
    D.3.2Product code APD334
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNetrasimod L-arginine
    D.3.9.1CAS number 1206123-97-8
    D.3.9.2Current sponsor codeAPD334 L-arginine
    D.3.9.3Other descriptive nameAR401959 L-arginine
    D.3.9.4EV Substance CodeSUB171412
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ulcerative Colitis
    Colitis Ulcerosa
    E.1.1.1Medical condition in easily understood language
    Ulcerative Colitis, a form of inflammatory bowel disease.
    Colitis ulcerosa como forma de enfermedad inflamatoria intestinal.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10045365
    E.1.2Term Ulcerative colitis
    E.1.2System Organ Class 100000004856
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10045366
    E.1.2Term Ulcerative colitis, unspecified
    E.1.2System Organ Class 100000004856
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of etrasimod when administered for 12 weeks on clinical remission in subjects with moderately to severely active ulcerative colitis (UC).
    Evaluar la eficacia de etrasimod en la remisión clínica cuando se administra durante 12 semanas en sujetos con colitis ulcerosa (CU) activa de moderada a grave
    E.2.2Secondary objectives of the trial
    The secondary objective is to assess the efficacy of etrasimod when administered for 12 weeks on clinical response, symptomatic response and remission, endoscopic changes, and mucosal healing in subjects with moderately to severely active UC.

    The safety objective is to assess the safety of etrasimod after daily doses of 2 mg for 12 weeks in subjects with moderately to severely active UC.

    Other objectives include evaluation of etrasimod pharmacokinetics (PK) and the effect of etrasimod on health related subject reported outcomes and biomarkers.
    El objetivo secundario es evaluar la eficacia de etrasimod cuando se administra durante 12 semanas, sobre la respuesta clínica, la respuesta y la remisión sintomáticas, los cambios endoscópicos y la cicatrización de la mucosa en sujetos con CU activa de moderada a grave.

    El objetivo de seguridad es evaluar la seguridad de etrasimod tras las dosis diarias de 2 mg durante 12 semanas en sujetos con CU activa de moderada a grave.

    Otros objetivos son la evaluación de la farmacocinética (FC) de etrasimod y el efecto de etrasimod sobre los resultados comunicados por el sujeto relacionados con la salud y los biomarcadores.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men, women and adolescents 16 to 80 years of age
    2. Ability to provide written informed consent or assent (parent or legal guardian must provide consent for a subject < 18 years of age who has assented to participate in the study or as required per local regulations) and to be compliant with the schedule of protocol assessments. Enrollment of
    subjects < 18 years should be conducted only if acceptable according to local laws and regulations.
    3. Diagnosed with UC ≥ 3 months prior to screening. The diagnosis of UC must be confirmed by endoscopic and histologic evidence. The endoscopy and histology report should be present in the source documents; however, if not available, the screening endoscopy and histology may serve as such
    4. Active UC confirmed by endoscopy with ≥ 10 cm rectal involvement. Inclusion of subjects with proctitis only at baseline will be capped at 15% of the total subjects enrolled.
    c. A male must agree to use condoms during treatment and for 4 weeks following treatment.
    5. Moderately to severely active UC defined as MMS of 4 to 9, including an ES of ≥ 2 and RB score ≥ 1
    6. Received a surveillance colonoscopy (performed according to local standard) within 12 months before baseline to rule out dysplasia in subjects with pancolitis > 8 years duration or subjects with left-sided colitis > 12 years duration. Subjects without a surveillance colonoscopy within the prior 12 months will have a colonoscopy at screening (ie, in place of screening proctosigmoidoscopy). Any adenomatous polyps must be removed prior to their first dose of study treatment.
    7. Demonstrated an inadequate response to, loss of response to, or intolerance to at least 1 of the following therapies as defined below:
    Conventional therapy
    a. Corticosteroids
    b. Thiopurines
    Biologic therapy or JAK inhibitor therapy
    a. Antitumor necrosis factor alpha (TNFα) antibodies (eg, infliximab, adalimumab, golimumab, or biosimilars)
    b. Anti integrin antibodies (eg, vedolizumab)
    c. JAK inhibitors (eg, tofacitinib)
    8. Subjects are permitted to be receiving a therapeutic dose of the following drugs:
    • Oral 5 ASA compounds provided the dose has been stable for ≥ 2 weeks immediately prior to randomization
    • Oral corticosteroid therapy (prednisone at a stable dose ≤ 20 mg/day, budesonide at a stable dose ≤ 9 mg/day, or equivalent steroid) provided the dose has been stable for the 4 weeks immediately prior to the screening endoscopy assessment
    • Immunosuppressive agents such as oral azathioprine or 6 mercaptopurine must be discontinued ≥ 2 weeks prior to randomization
    • Probiotics (eg, Culturelle®, Saccharomyces boulardii) provided the dose has been stable for the 2 weeks immediately prior to randomization
    • Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic diarrhea
    If oral aminosalicylates or corticosteroids have been recently discontinued, they must have been stopped for at least 2 weeks prior to the endoscopy used for the baseline MMS.
    9. Vital signs at screening and prerandomization taken in the sitting position: heart rate ≥ 50 bpm, systolic blood pressure (BP) ≥ 90 mm Hg, and diastolic BP ≥ 55 mm Hg
    10. Screening and prerandomization 12 lead electrocardiogram (ECG) showing no clinically significant abnormalities with a PR interval ≤ 200 ms, Fridericia’s corrected QT interval (QTcF) < 450 ms (men) or QTcF < 470 ms (women)
    11. Adequate hematological function
    12. Adequate hepatic function. Subjects with an isolated total bilirubin and normal AST and ALT diagnosed with Gilbert’s syndrome may participate
    13. Adequate renal function
    14. Females must meet either a or b of the following criteria and males must meet
    criterion c to qualify for the study:
    a. A female who is not of childbearing potential must meet 1 of the following:
    Postmenopausal, defined as no menses for 12 months without an alternative medical cause;
     Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.
    b. A female who is of childbearing potential must agree to use a highly effective contraception method during treatment, and for 4 weeks following treatment. The following are considered highly effective birth control methods include:
     Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, which may be oral, intravaginal, or transdermal.
     Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injected, or implanted.
     Intrauterine device.
     Intrauterine hormone-releasing system.
     Bilateral tubal occlusion.
     Vasectomized partner, provided that partner is the sole sexual partner of the WOCBP and that the vasectomized partner has received medical assessment of the surgical success.
    Sexual abstinence (complete sexual abstinence defined as refraining from heterosexual intercourse for the entire period of risk associated with study treatments).
    1. La población de estudio está formada por hombres, mujeres y adolescentes (a los que en este documento nos referiremos como hombres y mujeres) de 16 a 80 años, ambos inclusive, con CU activa de moderada a grave.
    2. Capacidad de proporcionar consentimiento informado por escrito o asentimiento (el progenitor o tutor legal debe dar su consentimiento para un sujeto <18 años que haya dado su asentimiento para participar en el estudio o según lo requerido por las normativas locales) y de cumplir el calendario de evaluaciones del protocolo. La inclusión de sujetos <18 años se debe producir solo si es aceptable de acuerdo con la normativa local.
    3. Diagnosticado con CU ≥3 meses antes de la selección. El diagnóstico de CU debe estar confirmado mediante pruebas endoscópicas e histológicas. Deben estar presentes en los documentos originales los informes de la endoscopia y la histología; sin embargo, si no están disponibles, la endoscopia y la histología de la selección pueden servir como tales.
    4. CU activa confirmada mediante endoscopia con afectación rectal ≥10 cm. La inscripción de sujetos con proctitis solo en el inicio se limitará al 15 % del total de sujetos inscritos.
    5. La CU activa de moderada a grave se define como MMS de 4 a 9, incluida una PE ≥2 y una puntuación de HR ≥1.
    6. Haberse sometido a una colonoscopia de vigilancia, de conformidad con la norma local, en los 12 meses anteriores al inicio para descartar displasia en los sujetos con pancolitis con una duración >8 años o sujetos con colitis del lado izquierdo con una duración >12 años. A los pacientes sin una colonoscopia de vigilancia en los 12 meses previos se les realizará una colonoscopia en la selección (es decir, en lugar de la proctosigmoidoscopia de selección). Cualquier pólipo adenomatoso debe eliminarse antes de la primera dosis del tratamiento del estudio.
    7. Mostró una respuesta inadecuada, pérdida de respuesta o intolerancia a, al menos, uno de los siguientes tratamientos, como se define a continuación:
    Tratamiento convencional
    a. Corticosteroides
    b. Tiopurinas
    Tratamiento biológico o tratamiento con inhibidores de JAK
    a. Anticuerpos del factor de necrosis tumoral alfa (TNFα) (p. ej., infliximab, adalimumab, golimumab o biosimilares)
    b. Anticuerpos anti-integrina (p. ej., vedolizumab)
    c. Inhibidores de JAK (p. ej., tofacitinib)
    8. Los sujetos pueden recibir una dosis terapéutica de los siguientes fármacos:
    • Compuestos de ácido 5-aminosalicílico (5-aminosalicylic acid, 5-ASA) por vía oral, siempre que la dosis se haya mantenido estable ≥2 semanas justo antes de la aleatorización.
    • Tratamiento con corticosteroides por vía oral (prednisona a una dosis estable ≤20 mg/día, budesonida a una dosis estable ≤9 mg/día o esteroide equivalente) siempre que la dosis se haya mantenido estable durante las 4 semanas inmediatamente antes de la evaluación de endoscopia de selección.
    • Los inmunodepresores tales como azatioprina o 6-mercaptopurina por vía oral se deben interrumpir ≥2 semanas antes de la aleatorización.
    • Probióticos (p. ej., Culturelle®, Saccharomyces boulardii), siempre que la dosis se haya mantenido estable durante las 2 semanas inmediatamente anteriores a la aleatorización.
    • Antidiarreicos (p. ej., loperamida, difenoxilato con atropina) para el control de la diarrea crónica.
    Si los aminosalicilatos o corticosteroides por vía oral se han interrumpido recientemente, deben haberse detenido durante al menos 2 semanas antes de la endoscopia para la MMS inicial.
    9. Constantes vitales en la selección y antes de la aleatorización tomadas en posición sentada: frecuencia cardíaca ≥50 lpm, TA sistólica ≥90 mmHg y TA diastólica ≥55 mmHg.
    10. Electrocardiograma de 12 derivaciones (ECG) en la selección y antes de la aleatorización que muestre ausencia de anomalías clínicamente significativas con un intervalo PR ≤200 ms, intervalo QT con la corrección de Fridericia (QTcF) <450 ms (hombres) o QTcF <470 ms (mujeres).
    11. Función hematológica adecuada, definida por un recuento de leucocitos ≥3,5 × 109/l, con un recuento absoluto de neutrófilos ≥1,5 ×109/l, recuento de linfocitos ≥0,8 × 109/l, recuento de plaquetas ≥100 x 109/l y hemoglobina ≥8 g/dl.
    12. Función hepática adecuada, definida por un nivel de bilirrubina total ≤1,5 x el rango del límite superior de la normalidad (LSN) y niveles de aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) ≤3,0 x LSN. Los sujetos con una bilirrubina total aislada y AST y ALT normales con diagnóstico de síndrome de Gilbert pueden participar.
    13. Función renal adecuada, definida por una tasa de filtración glomerular estimada ≥30 ml/min/1,73 m2 mediante la ecuación CKD-EPI en la selección.
    14. Las mujeres deben cumplir el criterio a o b de los siguientes y los hombres el criterio c para ser aptos para participar en el estudio:
    Por favor referirse al protocolo.

    E.4Principal exclusion criteria
    1. Severe extensive colitis as evidenced by:
    • Physician judgment that the subject is likely to require hospitalization for medical care or surgical intervention of any kind for UC (eg, colectomy) within 12 weeks of baseline
    • Current evidence of fulminant colitis, toxic megacolon or recent history (within last 6 months) of toxic megacolon, or bowel perforation
    • Previous total or partial colectomy
    2. Diagnosis of Crohn’s disease or indeterminate colitis or the presence or history of a fistula consistent with Crohn’s disease
    3. Diagnosis of microscopic colitis, ischemic colitis, or infectious colitis
    4. Hospitalization for exacerbation of UC requiring intravenous (IV) steroids within 12 weeks of screening (a single dose of IV steroids given is acceptable)
    5. Positive assay or stool culture for pathogens or positive test for Clostridium difficile toxin at screening
    6. Pregnancy, lactation, or a positive serum β hCG measured during screening
    7. Clinically relevant hematologic, hepatic, neurological, pulmonary, ophthalmological, endocrine, metabolic, psychiatric or other major systemic disease making implementation of the protocol or interpretation of the study difficult or would put the subject at risk
    8. Recent history (within 6 months of the Screening) of cardiovascular disease, including myocardial infarction or unstable angina, stroke/ transient ischemic attack, decompensated heart failure (requiring inpatient treatment), or New York Heart Association Class III/IV heart failure
    9. Any history of the following, unless treated with an implanted pacemaker or an implanted cardioverter-defibrillator with pacing:
    • History or presence of symptomatic bradycardia
    • History of sick sinus syndrome or neurocardiogenic syncope
    • Second or third degree AV block
    • Periods of asystole > 3 seconds
    10. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) < 70% of predicted values and FEV1/FVC ratio < 0.70 at screening
    11. Uncontrolled diabetes at screening, or subjects with diabetes with significant comorbid conditions such as retinopathy
    12. History of macular edema or retinopathy
    13. Current or past history of active tuberculosis (TB), history of untreated latent TB infection, or test positive for latent TB infection at screening.
    14. Known active bacterial, viral, fungal, mycobacterial infection, or other infection or any major episode of infection that required hospitalization or treatment with IV antibiotics within 30 days of screening or during screening or oral antibiotics within 14 days prior to screening. Fungal infection of nail beds is allowed
    15. Have HIV/acquired immune deficiency syndrome or test positive for HIV antibodies at screening
    16. Have acute or chronic hepatitis B infection or test positive for hepatitis B virus (HBV) at screening
    17. Have current hepatitis C infection or test positive for hepatitis C virus (HCV) at screening
    18. History of an opportunistic infection (eg, pneumocystis carinii, cryptococcal meningitis, progressive multifocal leukoencephalopathy) or serious bacterial, viral, or fungal infections (eg, disseminated herpes simplex, disseminated herpes zoster) requiring IV medication(s) ≤ 3 weeks prior to randomization
    19. History of or currently active primary or secondary immunodeficiency
    20. History of cancer within the last 5 years, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been excised and resolved) or colonic mucosal dysplasia
    21. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma
    22. History of alcohol or drug abuse within 1 year of randomization
    23. Hypersensitivity to etrasimod or any of the excipients or placebo compounds
    24. Prior treatment with sphingosine 1 phosphate receptor modulators
    25. Treatment with a biologic agent within 8 weeks or 5 elimination half lives, prior to randomization
    26. Treatment with an investigational therapy within 3 months prior to randomization
    27. Treatment failure with ≥ 3 biologic agents or ≥ 2 biologics plus a JAK inhibitor
    28. Treatment with topical rectal 5 ASA, short chain fatty acid enemas, or steroids within 2 weeks of screening or during screening
    29. Treatment with cyclosporine, tacrolimus, sirolimus, methotrexate, or mycophenolate mofetil within 16 weeks of screening
    30. Receipt of a live vaccine within 4 weeks prior to randomization
    31. Previous treatment with natalizumab
    32. Previous treatment with lymphocyte-depleting therapies
    33. Previous treatment with D penicillamine, leflunomide, or thalidomide
    34. Treatment with IV immune globulin or plasmapheresis within 3 months prior to randomization
    35. Chronic use of therapies that moderately/strongly inhibit/induce cytochrome P450 (CYP) 2C8 and 2C9 metabolism and inhibitors of UGT1A7 within 4 weeks prior to randomization.
    1. Colitis extensa grave observada mediante:
    • Criterio médico de que el sujeto es probable que requiera hospitalización para atención médica o una intervención quirúrgica de cualquier tipo para la CU (p. ej., colectomía) en las 12 semanas previas al inicio.
    • Pruebas actuales de colitis fulminante, megacolon tóxico o antecedentes recientes (en los últimos 6 meses) de megacolon tóxico o perforación intestinal.
    • Colectomía total o parcial previa.
    2. Diagnóstico de enfermedad de Crohn o colitis indeterminada, o presencia o antecedentes de una fístula coherente con la enfermedad de Crohn.
    3. Diagnóstico de colitis microscópica, colitis isquémica o colitis infecciosa.
    4. Hospitalización por una exacerbación de la CU que requiere esteroides i.v. en las 12 semanas previas a la selección (una sola dosis administrada de esteroides i.v. es aceptable).
    5. Resultado positivo en ensayo o cultivo de heces (análisis de huevos y parásitos, bacterias) o resultado positivo en una prueba de toxinas de Clostridium difficile en la selección (si C. Difficile es positivo, el sujeto puede ser tratado y repetirse la prueba ≥4 semanas después de la finalización del tratamiento).
    6. Embarazo, lactancia o resultado positivo de gonadotropina coriónica humana beta en suero determinados en la selección.
    7. Enfermedad hematológica, hepática, neurológica, pulmonar, oftalmológica, endocrina, metabólica (por ejemplo, hipo e hiperpotasiemia), psiquiátrica u otra enfermedad sistémica importante, clínicamente relevantes, que dificulten la aplicación del protocolo, la interpretación del estudio o que pudieran poner en riesgo al sujeto.
    8. Antecedentes recientes (en los 6 meses previos a la visita de selección) de enfermedad cardiovascular, incluidos infarto de miocardio, angina inestable accidente cerebrovascular/ ataque isquémico transitorio, insuficiencia cardíaca descompensada (que requiere tratamiento hospitalario) o insuficiencia cardíaca de clase III / IV de la Asociación de Cardiología de Nueva York.
    9. Cualquiera de los siguientes antecedentes, a menos que estén tratados con un marcapasos implantado o un desfibrilador cardioversor con estimulación implantado:
    • Antecedentes o presencia de bradicardia sintomática.
    • Antecedentes de síndrome de disfunción sinusal o síncope neurocardiogénico.
    • Bloqueo auriculoventricular (AV) de segundo o tercer grado.
    • Periodos de asistolia >3 segundos.
    10. Volumen espiratorio forzado en 1 segundo (VEF1) o capacidad vital forzada (CVF) <70 % de los valores previstos y cociente VEF1/CVF <0,70 en la selección.
    11. Diabetes no controlada, determinada por una hemoglobina A1c (HbA1c) >9 % en la selección, o sujetos con diabetes y comorbilidades significativas, como retinopatía.
    12. Antecedentes de edema macular o retinopatía.
    13. Tratamiento actual o antecedentes de tuberculosis (TB) activa, antecedentes de infección de TB latente no tratada o un resultado positivo en la prueba de infección de TB latente en la selección. Las siguientes son EXCEPCIONES a este criterio de exclusión:
    • Los sujetos con TB latente, en los que se haya descartado la TB activa, que hayan completado un ciclo adecuado de tratamiento de profilaxis de TB, según las directrices clínicas nacionales/locales o las directrices de la OMS y que no hayan tenido contacto cercano reciente con una persona con TB activa, son aptos para la inscripción en el estudio. Es responsabilidad del investigador comprobar la idoneidad del tratamiento anterior para la TB y aportar la documentación pertinente.
    • Los sujetos con diagnóstico de TB latente en la selección en los que se haya descartado la TB activa y que hayan recibido al menos 4 semanas de un régimen de profilaxis adecuado para la TB, pueden volver a someterse al proceso de selección para su inscripción.
    Nota: Las dos excepciones a este criterio de exclusión descritas anteriormente NO se aplican a los sujetos de países identificados por la OMS como de elevada carga de TB resistente, debido al alto riesgo de infección latente con resistencia a múltiples fármacos.
    14. Infección bacteriana, vírica, fúngica, micobacteriana activa conocida u otro tipo de infección (incluida TB o enfermedad micobacteriana atípica) o cualquier episodio importante de infección que requiera hospitalización o tratamiento con antibióticos por vía i.v. en los 30 días anteriores a la selección o durante la selección o antibióticos por vía oral en los 14 días anteriores a la selección. Se permite la infección fúngica del lecho ungueal.
    15. Tener el virus de inmunodeficiencia adquirida (VIH)/síndrome de inmunodeficiencia adquirida o un resultado positivo en la prueba de anticuerpos de VIH en la selección.
    Por favor referirse al protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoints will evaluate etrasimod versus placebo in:
    • The proportion of subjects in clinical remission at Week 12
    Los puntos finales de eficacia primarios evaluarán etrasimod versus placebo en
    • La proporción de sujetos con remisión clínica en la semana 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    semana 12
    E.5.2Secondary end point(s)
    The key secondary efficacy endpoints are:
    • The proportion of subjects achieving endoscopic improvement at Week 12
    • Proportion of subjects with mucosal healing at Week 12

    The other secondary endpoints are:
    • Proportion of subjects with a clinical response at Week 12
    • Proportion of subjects with endoscopic improvement at Week 12
    • Proportion of subjects with endoscopic normalization at Week 12
    • Proportions of subjects with clinical response of RB and SF symptom outcomes at each of the following time points: Weeks 2, 4, 8, and 12
    • Proportions of subjects with clinical remission of RB and SF symptom outcomes at each of the following time points: Weeks 2, 4, 8, and 12

    Exploratory efficacy endpoints are:
    • Proportion of subjects with remission and response using total Mayo Clinic score at Weeks 12
    • Proportion of subjects with histologic remission at Week 12 (as defined by the Geboes, Robarts, and Nancy histopathology scores)
    • Proportion of subjects with histologic improvement at Week 12 (as defined by the Geboes, Robarts, and Nancy histopathology scores)
    • Proportion of subjects with improvement in EIMs at Weeks 12 in subjects with EIMs at baseline

    Other Efficacy Related Endpoints
    Health Related Quality of Life
    • Scores and change from baseline to Week 12 in the following:
    - IBDQ total score
    - UC PRO/SS
    - SF 36, version 2, physical and mental component and domain scores
    - WPAI-UC
    - Urgency NRS
    - Abdominal pain NRS
    • Proportion of subjects with UC-related hospitalizations
    • Proportion of subjects requiring UC-related surgeries, including colectomy

    • Plasma concentrations of etrasimod, M3 (AR503641), and other metabolite(s) of interest (if warranted) will be assessed from samples collected prior to dosing and 4 hours (± 15 minutes) post dose (after 12-lead ECG) on Week 0/Day 1
    • Plasma concentrations of etrasimod, M3 (AR503641), and other metabolite(s) of interest (if warranted) will be assessed from samples collected prior to dosing (trough) at Weeks 2, 4, 8, and 12

    • Change from baseline in level of fecal calprotectin at Weeks 4, 8, and 12
    • Change from baseline in level of hs CRP at Weeks 2, 4, 8, and 12
    • Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, and 12

    Safety Endpoints
    • Incidence and severity of adverse events
    • Incidence and severity of laboratory abnormalities, and change from baseline in laboratory values (to include hematology, serum chemistry, coagulation, and urinalysis)
    • Incidence of clinically significant vital sign abnormalities and changes from baseline
    Criterios de valoración secundarios clave de la eficacia:
    • La proporción de sujetos que consigan una mejoría endoscópica en la semana 12.
    • La proporción de sujetos con cicatrización de la mucosa en la semana 12.

    Los otros puntos finales secundarios son:
    • Proporción de sujetos con respuesta clínica en la semana 12
    • Proporción de sujetos con mejoría endoscópica en la semana 12
    • Proporción de sujetos con normalización endoscópica en la semana 12
    • Proporciones de sujetos con respuesta clínica de resultados de síntomas de BR y SF en cada uno de los siguientes puntos de tiempo: semanas 2, 4, 8 y 12
    • Proporciones de sujetos con remisión clínica de resultados de síntomas de BR y SF en cada uno de los siguientes puntos de tiempo: semanas 2, 4, 8 y 12

    Los puntos finales de eficacia exploratoria son:
    • Proporción de sujetos con remisión y respuesta usando el puntaje total de Mayo Clinic en las semanas 12
    • Proporción de sujetos con remisión histológica en la semana 12 (según lo definido por los puntajes de histopatología de Geboes, Robarts y Nancy)
    • Proporción de sujetos con mejoría histológica en la semana 12 (según lo definido por los puntajes de histopatología de Geboes, Robarts y Nancy)
    • Proporción de sujetos con mejoría en EIM en las semanas 12 en sujetos con EIM al inicio

    Otros puntos finales relacionados con la eficacia
    Calidad de vida relacionada con la salud
    • Puntuaciones y cambios desde el inicio hasta la semana 12 en lo siguiente:
    - Puntaje total IBDQ
    - UC PRO / SS
    - SF 36, versión 2, componente físico y mental y puntajes de dominio
    - WPAI-UC
    - Urgencia NRS
    - Dolor abdominal NRS
    • Proporción de sujetos con hospitalizaciones relacionadas con la UC.
    • Proporción de sujetos que requieren cirugías relacionadas con la CU, incluida la colectomía.

    • Las concentraciones plasmáticas de etrasimod, M3 (AR503641) y otros metabolitos de interés (si está justificado) se evaluarán a partir de muestras recolectadas antes de la dosificación y 4 horas (± 15 minutos) después de la dosis (después del ECG de 12 derivaciones) en Semana 0 / Día 1
    • Las concentraciones plasmáticas de etrasimod, M3 (AR503641) y otros metabolitos de interés (si está justificado) se evaluarán a partir de muestras recolectadas antes de la dosificación (mínimo) en las semanas 2, 4, 8 y 12.

    • Cambio desde el valor basal en el nivel de calprotectina fecal en las semanas 4, 8 y 12
    • Cambio desde la línea de base en el nivel de hs CRP en las semanas 2, 4, 8 y 12
    • Cambio y cambio porcentual desde el inicio en el recuento de linfocitos en las semanas 2, 4, 8 y 12

    Puntos finales de seguridad
    • Incidencia y gravedad de los eventos adversos.
    • Incidencia y gravedad de las anormalidades de laboratorio, y cambios desde el valor basal en los valores de laboratorio (para incluir hematología, química sérica, coagulación y análisis de orina)
    • Incidencia de anomalías de signos vitales clínicamente significativos y cambios desde el inicio
    E.5.2.1Timepoint(s) of evaluation of this end point
    Weeks 2, 4, 8, and 12
    Semanas 2, 4, 8 y 12
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA253
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Czech Republic
    Korea, Republic of
    Moldova, Republic of
    Russian Federation
    South Africa
    United Kingdom
    United States
    E.8.7Trial 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
    última visita, último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 10
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 290
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 126
    F.4.2.2In the whole clinical trial 330
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    NONE. However eligible participants will be given the opportunity to enter an open label extension study (OLE) with etrasimod
    NINGUNO Sin embargo, los participantes elegibles tendrán la oportunidad de participar en un estudio de extensión de etiqueta abierta (OLE) con etrasimod
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-02-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-15
    P. End of Trial
    P.End of Trial StatusOngoing
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