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    Summary
    EudraCT Number:2017-000617-23
    Sponsor's Protocol Code Number:SHP647-307
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-05-14
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-000617-23
    A.3Full title of the trial
    A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Study of SHP647 as Maintenance
    Therapy in Subjects With Moderate to Severe Crohn’s Disease (CARMEN CD 307)
    Estudio de fase 3, aleatorizado, doble ciego, controlado con placebo y de grupos paralelos para evaluar la eficacia y la seguridad de SHP647 como tratamiento de mantenimiento en sujetos con enfermedad de Crohn de moderada a grave (CARMEN CD 307)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Research study to determine whether an investigational drug, SHP647, is safe and effective in the treatment of moderate to severe Crohn’s Disease, compared with placebo (dummy treatment) – using a randomised and blinded study design (investigator and patients are not aware whether they receive study drug or placebo.
    Estudio de investigación para determinar si el producto en investigación, SHP647, es seguro y efectivo en el tratamiento de la Enfermedad de Crohn moderada o severa, comparado con placebo (tratamiento sin medicamento) se usará un diseño de aleatorización y ciego (ni el médico ni los pacientes participantes sabrán si reciben el medicamento o el placebo
    A.3.2Name or abbreviated title of the trial where available
    CARMEN CD 307
    A.4.1Sponsor's protocol code numberSHP647-307
    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 SponsorShire Human Genetic Therapies, 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 supportShire Human Genetic Therapies, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShire Human Genetic Therapies, Inc.
    B.5.2Functional name of contact pointMelanie Ivarsson
    B.5.3 Address:
    B.5.3.1Street Address300 Shire Way
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34900834223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.com
    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 nameSHP647
    D.3.2Product code SHP647
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAnti-MAdCAM antibody
    D.3.9.2Current sponsor codeSHP647
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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 Yes
    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.IMP: 2
    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 nameSHP647
    D.3.2Product code SHP647
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAnti-MAdCAM antibody
    D.3.9.2Current sponsor codeSHP647
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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 Yes
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Crohn's disease
    Enfermedad de Crohn
    E.1.1.1Medical condition in easily understood language
    Long-term condition that results in inflammation of the gastrointestinal tract
    Enfermedad crónica que produce inflamación en el tracto gastrointestinal
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10011402
    E.1.2Term Crohn's disease (colon)
    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
    The coprimary objectives of the study are to evaluate the efficacy of SHP647 as maintenance
    treatment in subjects with moderate to severe Crohn's Disease (CD) based on:
    -Clinical remission based on 2-item patient-reported outcome (PRO) (abdominal pain
    severity and very soft stool/liquid stool frequency)
    -Enhanced endoscopic response based on centrally read colonoscopy.
    Los objetivos principales de este estudio consisten en evaluar la eficacia de SHP647 como tratamiento de mantenimiento en sujetos con enfermedad de Crohn (EC) de moderada a grave en cuanto a:
    •Remisión clínica según un resultado comunicado por los pacientes (RCP) de dos apartados (intensidad del dolor abdominal y frecuencia de deposiciones muy blandas/líquidas).
    •Respuesta endoscópica mejorada según una colonoscopia evaluada de forma centralizada.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of SHP647 as maintenance treatment:
    -on clinical remission as measured by Crohn's Disease Activity Index (CDAI)
    -on glucocorticoid-free clinical remission based on patient-reported clinical signs and symptoms (as measured by 2-item PRO)
    -on clinical remission based on abdominal pain severity and very soft stool/liquid stool frequency (alternate thresholds)
    -based on achieving clinical remission as well as achieving enhanced endoscopic response in the same subject
    -on complete endoscopic healing.
    To evaluate the efficacy of SHP647 on maintenance:
    -of clinical remission among subjects in clinical remission at baseline of the SHP647-307 study based on patient-reported clinical signs and symptoms (as measured by 2-item PRO)
    -of enhanced endoscopic response among subjects with enhanced endoscopic response at baseline of the SHP647-307 study based on centrally read colonoscopy
    Evaluar la eficacia de SHP647 como tratamiento de mantenimiento en cuanto a:
    •Remisión clínica según puntuación del Índice de actividad de la enfermedad de Crohn (CDAI).
    •Remisión clínica sin glucocorticoides según los signos y síntomas clínicos comunicados por los pacientes utilizando un RCP de 2 apartados
    •Remisión clínica según intensidad del dolor abdominal y frecuencia de deposiciones muy blandas/líquidas (umbrales alternos).
    •Los logros de remisión clínica y de una respuesta endoscópica mejorada en el mismo sujeto
    •La curación endoscópica completa
    Evaluar la eficacia de SHP647 en cuanto al mantenimiento de:
    •Remisión clínica en sujetos con remisión clínica en el momento basal del estudio SHP647-307 según los signos y síntomas clínicos comunicados por los pacientes utilizando un RCP de dos apartados
    •Respuesta endoscópica mejorada en sujetos con respuesta endoscópica mejorada en el momento basal del estudio SHP647-307, según una colonoscopia evaluada de forma centralizada
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects and/or their parent or legally authorized representative must have an understanding, ability, and willingness to fully comply with study procedures and restrictions.
    2. Subjects must be able to voluntarily provide written, signed, and dated (personally or via a legally authorized representative) informed consent and/or assent, as applicable, to participate in the study.
    3. Subjects must have completed the 16-week induction treatment period from study
    SHP647-305 or SHP647-306 and met the following criteria at baseline in maintenance Study SHP647-307:
    a) Meet endoscopic response criteria of a reduction in SES-CD from induction study
    (SHP647-305 or SHP647-306) baseline by ≥25% at Week 16 of induction study (SHP647-305 or SHP647-306)
    OR
    b) Meet at least 1 of the following 4 criteria at baseline in maintenance study SHP647-307, in addition to no worsening of endoscopic score as measured by SES-CD relative to induction study (SHP647-305 or SHP647-306) baseline:
    i. Achieving clinical remission as determined by meeting the criteria for clinical
    remission using the 2-item PRO, ie, 2-item PRO subscores of average worst daily
    abdominal pain ≤3 (based on 11-point numerical rating scale [NRS]) over the 7 most
    recent days* and average daily stool type frequency ≤2 of type 6/7 (very soft
    stools/liquid stools) as shown in the BSFS over the 7 most recent days*
    ii. A decrease of at least 70 points in CDAI score (CDAI-70) from induction study
    (SHP647-305 or SHP647-306) baseline.
    iii. A decrease of ≥30% and at least 2 points from induction study (SHP647-305 or
    SHP647-306) baseline in the average daily worst abdominal pain over the 7 most
    recent days*, with the average daily stool frequency of type 6/7 (very soft
    stools/liquid stools) either: (i) not worsening from induction study (SHP647-305 or
    SHP647-306) baseline and/or (ii) meeting the criteria for clinical remission,
    ie, 2-item PRO subscore of average daily stool frequency ≤2 of type 6/7 (very soft
    stools/liquid stools) as shown in the BSFS over the 7 most recent days*
    iv. A decrease of ≥30% from induction study (SHP647-305 or SHP647-306) baseline in
    the average daily stool frequency of type 6/7 (very soft stools/liquid stools) as shown
    in the BSFS over the 7 most recent days*, with the average daily worst abdominal
    pain either: (i) not worsening from induction study (SHP647-305 or SHP647-306)
    baseline and/or (ii) meeting the criteria for clinical remission, ie, 2-item PRO
    subscore of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the
    7 most recent days*
    *Note: The 7 days may or may not be contiguous during the 10 days of data
    collection before colonoscopy preparation, depending on days to be excluded because
    of missing data. If fewer than 7 days are available, the criterion will be calculated on
    all available most recent 6 or 5 days. If fewer than 5 days are available, the criterion
    will be treated as missing.
    4. Subjects receiving any treatment(s) for CD are eligible provided they have been, and are anticipated to be, on a stable dose for the designated period of time.
    1. El sujeto o sus padres o representante legal deben mostrar entendimiento, capacidad y disposición para cumplir totalmente los procedimientos y restricciones del estudio.
    2. El sujeto debe ser capaz de otorgar voluntariamente su consentimiento y/o asentimiento informado por escrito, firmado y fechado (personalmente o a través de un representante legal).
    3. Los sujetos deberán haber completado el período de tratamiento de inducción de 16 semanas del estudio SHP647-305 o SHP647-306 y cumplir los criterios siguientes en el momento basal del estudio de mantenimiento SHP647-307:
    a) Cumplir los criterios de respuesta endoscópica de una reducción ≥25% de la puntuación endoscópica simple para la EC (SES-CD) entre el momento basal y la semana 16 del estudio de inducción (SHP647-305 o SHP647-306).
    O
    b) Cumplir al menos 1 de los 4 criterios siguientes en el momento basal del estudio de mantenimiento SHP647-307, además de ausencia de empeoramiento de la puntuación endoscópica determinada mediante el SES-CD respecto al momento basal del estudio de inducción (SHP647-305 o SHP647-306):
    i. Lograr la remisión clínica, determinada por el cumplimiento de los criterios de remisión clínica utilizando el RCP de 2 apartados, es decir, subpuntuaciones ≤ 3 en el RCP de 2 apartados para el promedio del peor dolor abdominal diario (utilizando una escala de valoración numérica [EVN] de 11 puntos) en los 7 días más recientes* y una frecuencia diaria promedio ≤ 2 del tipo 6/7 de deposiciones de la BSFS (heces muy blandas/heces líquidas) en los 7 días más recientes*.
    ii. Disminución de al menos 70 puntos en la puntuación CDAI (CDAI-70) respecto al momento basal del estudio de inducción (SHP647-305 o SHP647-306).
    iii. Disminución ≥ 30% y ≥ 2 puntos con respecto al momento basal del estudio de inducción (SHP647-305 o SHP647-306) en el promedio de peor dolor abdominal diario durante los 7 días más recientes*; además, la frecuencia diaria promedio de deposiciones de tipo 6/7 (deposiciones muy blandas/líquidas):
    (i) que no haya empeorado con respecto al momento basal del estudio de inducción (SHP647-305 o SHP647-306) o
    (ii) que cumpla los criterios de remisión clínica, con una subpuntuación ≤ 2 en el RCP de 2 apartados para la frecuencia diaria promedio del tipo 6/7 de deposiciones de la BSFS (heces muy blandas/heces líquidas) en los 7 días más recientes*.
    iv. Disminución ≥ 30% con respecto al momento basal del estudio de inducción (SHP647-305 o SHP647-306) en la frecuencia diaria promedio de deposiciones de tipo 6/7 (deposiciones muy blandas/líquidas) según la escala BSFS, durante los 7 días más recientes*; además, el promedio de peor dolor abdominal diario: (i) no haya mostrado empeoramiento con respecto al momento basal del estudio de inducción (SHP647-305 o SHP647-306) o (ii) que cumpla los criterios de remisión clínica, es decir, con una subpuntuación en el RCP de dos apartados para el promedio de peor dolor abdominal diario ≤ 3 (según la EVN de 11 puntos) en los 7 días más recientes*.
    *Nota: Los 7 días más recientes podrán ser o no contiguos durante los 10 días de recogida de datos antes de la preparación para la colonoscopia, dependiendo de los días a descartar por falta de datos. Cuando se disponga de datos correspondientes a menos de 7 días, el criterio de valoración se calculará con todos los datos disponibles correspondientes a los 6 o 5 días más recientes. Cuando se disponga de datos correspondientes a menos de 5 días, el criterio de valoración se considerará omitido.
    4. Los sujetos que estén recibiendo alguno de los tratamientos para la EC que se describen en la sección 5.2.1 del protocolo podrán participar siempre que la dosis sea estable y esté previsto mantenerla durante el período especificado.
    E.4Principal exclusion criteria
    1. Subjects who had major protocol deviation(s) (as determined by the sponsor) in induction study SHP647-305 or SHP647-306.
    2. Subjects who permanently discontinued investigational product because of an AE, regardless of relatedness to investigational product, in induction study SHP647-305 or SHP647-306.
    3. Subjects who are likely to require surgery for CD during the study period, except minor interventions (eg, seton placement for anal fistulas).
    4. Subjects are females who became pregnant during induction study SHP647-305 or SHP647-306, females who are planning to become pregnant during the study period, or males or females of childbearing potential not agreeing to continue using appropriate contraception methods through the conclusion of study participation.
    5. Male subjects who are planning to donate sperm and do not agree not to do so for the duration of the study and through 16 weeks after last dose of investigational product.
    6. Subjects who, in the opinion of the investigator or the sponsor, will be uncooperative or unable to comply with study procedures.
    7. Subjects who have developed obstructive colonic stricture during the induction studies (SHP647-305 or SHP647-306).
    8. Subjects who have a newly diagnosed malignancy or recurrence of malignancy (other than resected cutaneous basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the uterine cervix that has been treated with no evidence of recurrence).
    9. Subjects who have developed any major illness/condition or evidence of an unstable clinical condition (eg, renal, hepatic, hematologic, gastrointestinal [except disease under study], endocrine, cardiovascular, pulmonary, immunologic [eg, Felty’s syndrome], or local active infection/infectious illness) that, in the investigator’s judgment, will substantially increase the risk to the subject if he or she participates in the study. 10. Subjects with any other severe acute or chronic medical or psychiatric condition or laboratory or electrocardiogram (ECG) abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
    11. Subjects with known exposure to Mycobacterium tuberculosis since testing at screening in induction study SHP647-305 or SHP647-306 and who have been advised to require treatment for latent or active disease but who are without a generally accepted course of treatment.
    12. Subjects with any of the following abnormalities in hematology and/or serum chemistry profiles during the evaluation of the last visit in the SHP647-305 or SHP647-306 studies. If the results are considered by the investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated once prior to enrolment in Study SHP647-307.
    -Alanine aminotransferase and aspartate aminotransferase levels ≥2.5 times the upper limit of normal (ULN) 
    Total bilirubin level ≥1.5 times the ULN (except where attributed to elevation in unconjugated bilirubin in subjects with documented diagnosis of Gilbert’s syndrome) 
    -Hemoglobin level ≤80 g/L (8.0 g/dL) 
    - Platelet count ≤100 × 109/L (100,000 cells/mm3) or ≥1000 × 109/L (1,000,000 cells/mm3) 
    - White blood cell count ≤3.5 × 109/L (3500 cells/mm3) 
    - Absolute neutrophil count<2 × 109/L (<2000 cells/mm3) 
    - Serum creatinine level >1.5 times the ULN or estimated glomerular filtration rate <30 mL/min/1.73 m2 based on the abbreviated Modification of Diet in Renal Disease Study Equation.
    13. Subjects who are investigational site staff members or relatives of those site staff members or subjects who are sponsor employees directly involved in the conduct of the study.
    14. Subjects who are participating in other investigational studies (other than induction study SHP647-305 or SHP647-306) or plan to participate in other investigational studies during Study SHP647-307
    1. Sujetos con alguna desviación importante del protocolo (a juicio del promotor) en el estudio de inducción SHP647-305 o SHP647-306.
    2. Sujetos que hayan suspendido de forma permanente el producto en investigación a causa de un acontecimiento adverso (AA), relacionado o no con el producto en investigación, en el estudio de inducción SHP647-305 o SHP647-306.
    3. Sujetos que probablemente vayan a necesitar cirugía para la EC durante el período del estudio, excepto intervenciones menores (p. ej., colocación de setones para fístulas anales).
    4. Mujeres que se quedaran embarazadas durante el estudio de inducción SHP647-305 o SHP647-306, mujeres que tengan intención de quedarse embarazadas durante el periodo del estudio y varones o mujeres con capacidad reproductiva que no acepten usar métodos anticonceptivos apropiados hasta el final de su participación en el estudio.
    5. Varones que tengan intención de donar semen y no se comprometan a no hacerlo durante el estudio y hasta 16 semanas después de la última dosis del producto en investigación.
    6. Sujetos que, en opinión del investigador, no serían cooperativos o serían incapaces de cumplir los procedimientos del estudio.
    7. Sujetos que hayan desarrollado estenosis obstructivas del colon durante los estudios de inducción (SHP647-305 o SHP647-306).
    8. Sujetos que tengan una neoplasia maligna recién diagnosticada o recurrente (distinto de carcinoma basocelular cutáneo o carcinoma epidermoide resecados o de carcinoma cervico uterino in situ tratado y sin signos de recidiva).
    9. Sujetos que hayan desarrollado una enfermedad/afección importante o indicios de enfermedad inestable (p. ej., renal, hepática, gastrointestinal [excepto la enfermedad en estudio], endocrina, cardiovascular, pulmonar, inmunitaria [p. ej., síndrome de Felty] o infección activa local/enfermedad infecciosa) que, en opinión del investigador, aumente considerablemente el riesgo para el sujeto en caso de participar en el estudio.
    10. Sujetos con cualquier otro trastorno médico o psiquiátrico grave, agudo o crónico, o cualquier alteración analítica o electrocardiográfica (ECG) que pueda aumentar el riesgo asociado a la participación en el estudio o a la administración del producto en investigación, o que pueda interferir en la interpretación de los resultados del estudio y, en opinión del investigador, impida la participación del paciente.
    11. Sujetos con exposición conocida a Mycobacterium tuberculosis desde las pruebas de selección del estudio de inducción SHP647-305 o SHP647-306 a los que se ha recomendado tratamiento para la enfermedad latente o activa pero que no reciben un régimen de tratamiento generalmente aceptado.
    12. Sujetos con alguna de las anomalías siguientes en los parámetros de hematología o bioquímica sérica durante la evaluación de la última visita en los estudios SHP647-305 o SHP647-306. Los análisis podrán repetirse una vez antes de la inclusión en el estudio SHP647-307 si el investigador considera que los resultados son transitorios y no concuerdan con la situación clínica del sujeto.
    • Alanina aminotransferasa y aspartato aminotransferasa ≥ 2,5 veces el límite superior de la normalidad (LSN).
    • Concentración de bilirrubina total ≥ 1,5 veces el LSN (excepto cuando se atribuya a una elevación de la bilirrubina no conjugada en sujetos con diagnóstico documentado de síndrome de Gilbert).
    • Hemoglobina ≤ 80 g/l (8,0 g/dl).
    • Recuento de plaquetas ≤ 100 × 109/l (100.000 células/mm3) o ≥ 1000 × 109/l (1.000.000 células/mm3).
    • Recuento de leucocitos ≤ 3,5 x 109/l (3500 células/mm3).
    • Recuento absoluto de neutrófilos < 2 × 109/l (< 2000 células/mm3).
    • Concentración sérica de creatinina > 1,5 veces el LSN o filtración glomerular estimada < 30 ml/min/1,73 m2 según la ecuación abreviada del estudio Modification of Diet in Renal Disease.
    13. Sujetos que formen parte del personal del centro de investigación o sean familiares de estos, o sujetos que sean empleados del promotor directamente involucrados en la realización del estudio.
    14. Sujetos que estén participando en otros estudios de investigación (distintos de los estudios de inducción SHP647-305 o SHP647-306) o tengan previsto hacerlo durante el estudio SHP647-307.
    E.5 End points
    E.5.1Primary end point(s)
    Coprimary efficacy endpoints are:
    -Clinical remission as defined by the following: 2- item PRO subscores of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days and average daily stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent days may or may not be contiguous during the 10 days of data collection before colonoscopy preparation, depending on days to be excluded because of missing data.
    If fewer than 7 days are available, the endpoint will be calculated on all
    available most recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as missing.
    -Enhanced endoscopic response as measured by a decrease in SES-CD of at least 50% from induction study (SHP647-305 or SHP647-306) baseline.
    Los criterios de valoración principales de la eficacia son:
    • Remisión clínica en la visita de la semana 52, definida por lo siguiente: subpuntuaciones ≤ 3 en el RCP de 2 apartados para el promedio del peor dolor abdominal diario (utilizando una EVN de 11 puntos) en los 7 días más recientes y una frecuencia diaria promedio ≤ 2 del tipo 6/7 de deposiciones de la BSFS (heces muy blandas/heces líquidas) en los 7 días más recientes. Los 7 días más recientes podrán ser o no contiguos durante los 10 días de recogida de datos antes de la preparación para la colonoscopia, dependiendo de los días a descartar por falta de datos. Cuando se disponga de datos correspondientes a menos de 7 días, el criterio de valoración se calculará con todos los datos disponibles correspondientes a los 6 o 5 días más recientes. Cuando se disponga de datos correspondientes a menos de 5 días, el criterio de valoración se considerará omitido.
    • Respuesta endoscópica mejorada en la semana 52, determinada por una disminución de la puntuación SES-CD de al menos el 50% con respecto al momento basal del estudio de inducción (SHP647-305 o SHP647-306).
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 52
    Semana 52
    E.5.2Secondary end point(s)
    •Clinical remission at the Week 52 visit as measured by CDAI <150

    • Glucocorticoid-free clinical remission at the Week 52 visit, among subjects using glucocorticoids at induction study baseline. Glucocorticoid-free clinical remission is defined as clinical remission by
    2-item PRO (as defined for the coprimary endpoint) in addition to not requiring any treatment with glucocorticoids

    • Clinical remission at the Week 52 visit as defined by the following: CD daily e-diary subscores of average worst daily abdominal pain ≤1 (based on the 4-point scale) over the 7 most recent days and average daily stool frequency ≤3 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent days may or may not be contiguous during the 10 days of data collection before colonoscopy preparation, depending on days to be excluded because of missing data. If fewer than 7 days are available, the endpoint will be calculated on all available most recent 6 or
    5 days. If fewer than 5 days are available, the endpoint will be treated as missing.

    • Sustained clinical remission, ie, in clinical remission at the SHP647-307 Week 52 visit, among subjects who were in clinical remission by 2-item PRO (as defined for the coprimary endpoint) at the time of baseline in Study SHP647-307

    • Sustained enhanced endoscopic response, ie, in enhanced endoscopic response at the SHP647-307
    Week 52 visit, among subjects who showed enhanced endoscopic response (as defined for the coprimary endpoint) at the time of baseline in Study SHP647-307

    • Both clinical remission by 2-item PRO and enhanced endoscopic response at Week 52 (composite endpoint)

    • Complete endoscopic healing at Week 52 defined as SES-CD=0-2.
    • Remisión clínica en la visita de la semana 52, determinada por una puntuación CDAI < 150.
    • Remisión clínica sin glucocorticoides en la visita de la semana 52, en los sujetos tratados con glucocorticoides en el momento basal del estudio de inducción. La remisión clínica sin glucocorticoides se define como remisión clínica según un RCP de 2 apartados (según la definición del criterio de valoración coprincipal), además de no precisar ningún tratamiento con glucocorticoides
    • Remisión clínica en la visita de la semana 52, definida por lo siguiente: subpuntuaciones diarias ≤ 1 (en una escala de 4 puntos) en el diario electrónico de la EC durante los 7 días más recientes y subpuntuación ≤ 3 de la frecuencia diaria promedio de deposiciones de tipo 6/7 (deposiciones muy blandas/líquidas), según la escala BSFS durante los 7 días más recientes. Los 7 días más recientes podrán ser o no contiguos durante los 10 días de recogida de datos antes de la preparación para la colonoscopia, dependiendo de los días a descartar por falta de datos. Cuando se disponga de datos correspondientes a menos de 7 días, el criterio de valoración se calculará con todos los datos disponibles correspondientes a los 6 o 5 días más recientes. Cuando se disponga de datos correspondientes a menos de 5 días, el criterio de valoración se considerará omitido.
    • Remisión clínica mantenida, es decir, en remisión clínica en la visita de la semana 52 del estudio SHP647-307, entre los sujetos que estaban en remisión clínica según un RCP de 2 apartados (conforme a la definición del criterio de valoración coprincipal) en el momento basal del estudio SHP647-307.
    • Respuesta endoscópica mejorada mantenida, es decir, respuesta endoscópica mejorada en la visita de la semana 52 del estudio SHP647-307 en los sujetos que presentaron una respuesta endoscópica mejorada (según la definición del criterio de valoración principal) en el momento basal del estudio SHP647-307.
    • Remisión clínica según un RCP de 2 apartados y respuesta endoscópica mejorada en la semana 52 (criterio de valoración compuesto).
    • Curación endoscópica completa en la semana 52, definida como una puntuación SES-CD = 0-2.
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 52
    Semana 52
    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 Yes
    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 No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of Life
    Calidad de vida
    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.7.1.3.1Other 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 Yes
    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 Yes
    E.8.2.3.1Comparator description
    25 mg or 75 mg SHP647
    E.8.2.4Number of treatment arms in the trial3
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA172
    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
    Argentina
    Australia
    Austria
    Belgium
    Bosnia and Herzegovina
    Brazil
    Bulgaria
    Canada
    Colombia
    Croatia
    Czech Republic
    Estonia
    France
    Germany
    Greece
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Lithuania
    Mexico
    Netherlands
    New Zealand
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    Slovakia
    South Africa
    Spain
    Switzerland
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    The Study Completion Date is defined as the date the final subject, across all sites, completes their final protocol-defined assessment.This includes the follow-up visit or contact, whichever is later.
    La fecha de finalización del estudio se define como la fecha en que el último sujeto, en todos los centros, completa su evaluación definitiva definida por el protocolo . Tenga en cuenta que ésto incluye la visita de seguimiento o contacto, lo que sea posterior
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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: 98
    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.1.1.6.1Number of subjects for this age range: 98
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 866
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 19
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Adolescents (16-17 years)
    Adolescentes (16-17 años)
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 499
    F.4.2.2In the whole clinical trial 983
    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)
    At the end of the treatment period (Week 52), the subject will either enter the long-term study (Study SHP647-304) if eligible, or the 16-week safety follow-up period with the SoC at investigator’ discretion.
    Al final del periodo de tratamiento de 52 semanas, el sujeto entrará bien al estudio SLP (SHP647 304) si es elegible, o bien a un periodo de seguimiento de la seguridad de 16 semanas con el tratamiento habitual a criterio de investigador
    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 Decision2018-07-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-21
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-09-13
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