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    Summary
    EudraCT Number:2016-004749-10
    Sponsor's Protocol Code Number:SP-1011-002
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-09-20
    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 number2016-004749-10
    A.3Full title of the trial
    FLUTicasone in Eosinophilic esophagitis (FLUTE): A Randomized, Double-blind, Placebo-controlled, Dose ranging, and Maintenance Study of APT-1011 in Subjects with Eosinophilic Esophagitis.
    FLUTicasona en la esofaguitis eosinofílica (FLUTE): estudio de mantenimiento, aleatorizado, doble ciego, controlado con placebo y de búsqueda de dosis de APT-1011 en sujetos con esofaguitis eosinofílica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    study in subjects with Eosinophilic Esophagitis
    Estudio en Sujetos con Esofagitis Eosinofíllica
    A.4.1Sponsor's protocol code numberSP-1011-002
    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 SponsorAdare Pharmaceutical
    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 supportAdare Pharmaceuticals
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQuintiles
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street AddressPlaza Building, 4820 Emperor Boulevard
    B.5.3.2Town/ cityDurham
    B.5.3.3Post code27703
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34934894035
    B.5.6E-mailensayosclinicos@quintiles.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 nameAPT-1011
    D.3.4Pharmaceutical form Orodispersible 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 INNFluticasone Propionate
    D.3.9.1CAS number 80474-14-2
    D.3.9.2Current sponsor codeAPT-1011
    D.3.9.3Other descriptive nameFLUTICASONE PROPIONATE
    D.3.9.4EV Substance CodeSUB02241MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.5
    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.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 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.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 nameAPT-1011
    D.3.4Pharmaceutical form Orodispersible 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 INNFluticasone Propionate
    D.3.9.1CAS number 80474-14-2
    D.3.9.2Current sponsor codeAPT-1011
    D.3.9.3Other descriptive nameFLUTICASONE PROPIONATE
    D.3.9.4EV Substance CodeSUB02241MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.5
    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.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 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.IMP: 3
    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 nameAPT-1011
    D.3.4Pharmaceutical form Orodispersible 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 INNFluticasone Propionate
    D.3.9.1CAS number 80474-14-2
    D.3.9.2Current sponsor codeAPT-1011
    D.3.9.3Other descriptive nameFLUTICASONE PROPIONATE
    D.3.9.4EV Substance CodeSUB02241MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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.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 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 placeboOrodispersible tablet
    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
    Eosinophilic Esophagitis
    Esofagitis Eosinofílica
    E.1.1.1Medical condition in easily understood language
    Eosinophilic Esophagitis
    Esofagitis Eosinofílica
    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 10064220
    E.1.2Term Eosinophilic esophagitis
    E.1.2System Organ Class 100000013492
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate the efficacy (histological response) of APT-1011 in adults with eosinophilic esophagitis (EoE).
    El objetivo principal del estudio es evaluar la eficacia (respuesta histológica) de APT-1011 en adultos con esofaguitis eosinofílica (EE).
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are as follows:
    • To define the dose-response of APT-1011;
    • To select a dose(s) of APT-1011 for Phase 3;
    • To evaluate the effect of APT-1011 on histology and endoscopic appearance;
    • To evaluate maintenance of efficacy and long-term safety of APT-1011;
    • To evaluate the population pharmacokinetics (PopPK) of APT-1011;
    • To evaluate the effect of APT-1011 on dysphagia episodes.
    Los objetivos secundarios del estudio son los siguientes:
     Definir la respuesta a la dosis de APT-1011.
     Seleccionar una dosis de APT-1011 para la fase III.
     Evaluar el efecto de APT-1011 sobre la histología y el aspecto endoscópico.
     Evaluar el mantenimiento de la eficacia y la seguridad a largo plazo de APT-1011.
     Evaluar la farmacocinética de la población (FCpob) de APT-1011.
     Evaluar el efecto de APT-1011 en los episodios de disfagia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must satisfy all of the following criteria:
    Before entering 4-week Baseline Symptom Assessment
    1. Male or female between ≥18 and ≤75 years of age at the time of informed consent;
    2. Signed the informed consent form (ICF) and willing and able to adhere to all study procedures;
    3. Diagnosis or presumptive diagnosis of EoE;
    • Diagnosis of EoE must be confirmed by symptoms, histology, and historical documentation of failed treatment on ≥8 weeks of high-dose proton pump inhibitors (PPI). For the purposes of FLUTE, high dose PPI is defined as 20 mg BID omeprazole or 20 to 40 BID mg of any marketed PPI; maintenance doses of PPIs are not acceptable. A lack of response to PPI therapy is defined as ≥15 PEAK eosinophils/HPF with at least 5 biopsies including both proximal and distal specimens after 8 weeks of high dose PPI treatment.
    • Documentation of PPI failure prior to initial diagnosis or by documentation of PPI failure at the time of Screening is required. The subjects may be pre-screened but should not be consented, sign an ICF, or be offered participation in FLUTE if they have not met the diagnostic criteria for EoE that requires that they fail an 8-week trial of high dose PPIs EXCEPT those that have taken PPIs for 8 weeks will use the EGD within the study for this documentation. The Investigator and potential subject must make the decision to complete a PPI trial independent of any considerations of the study. There is insufficient time to do the 8 week trial within the current study. Should a subject be consented in error and screen fails due to this point, they may be re screened as described in the protocol.
    4. Have a subject reported history of ≥3 episodes of dysphagia (difficulty with food going down) in the 7 days prior to Screening;
    5. Have a 7-day Global EoE Symptom Score >3 at baseline (EoE score must remain >3 at each of Visits 1, 2 and 3 before randomization). This will be performed on paper during the Screening visit.
    6. Willing and able to adhere to study related treatment regimens, procedures, and visit schedule.
    Before randomization
    7. To be determined prior to randomization: have evidence of EoE, as defined by ≥15 PEAK eosinophils/HPF. In order to ensure that a diagnosis can be made, at least 5-6 biopsies should be taken including both proximal and distal specimens (~3 each);
    • No EGDs and biopsies performed outside FLUTE are acceptable for meeting eligibility criteria.
    • Optional biopsies may be taken and processed locally for local use, if specified in the local ICF.
    • Biopsies are to be obtained PRIOR to the 4-week Baseline Symptom Assessment. Eligibility from a histological perspective will be based solely on the central pathologist’s assessment.
    8. To be determined prior to randomization: in the daily diary, report at least 3 episodes of dysphagia (difficulty with food going down) for each of the last 7 days during the last 14 days of the 4-week Baseline Symptom Assessment
    9. To be determined prior to randomization: completion of the daily diary on at least 5 out of each 7 days during the last 14 days of the 4-week Baseline Symptom Assessment.
    Los sujetos deben cumplir todos los criterios siguientes:
    Antes de entrar en la evaluación de los síntomas iniciales de 4 semanas
    1. Varones o mujeres entre ≥18 y ≤75 años de edad en el momento del consentimiento informado.
    2. Haber firmado el formulario de consentimiento informado (FCI) y estar dispuestos a cumplir todos los procedimientos del estudio y ser capaces de ello.
    3. Diagnóstico o presunción de diagnóstico de EE.
     El diagnóstico de EE debe confirmarse por los síntomas, la histología y la documentación histórica del fracaso del tratamiento con dosis altas de inhibidores de la bomba de protones (IBP) durante ≥8 semanas. A los efectos de FLUTE, una dosis alta de IBP se define como 20 mg dos veces al día de omeprazol o de 20 a 40 mg dos veces al día de cualquier otro IBP comercializado; no se aceptan las dosis de mantenimiento de IBP. Una falta de respuesta al tratamiento con IBP se define como una concentración máxima de eosinófilos ≥15/CGA con al menos 5 biopsias que incluyan tanto muestras proximales como distales tras 8 semanas de tratamiento con dosis altas de IBP.
    Confidential
    Spanish translation of SP-1011-002_Protocol Synopsis dated on 05 May 2017
     Es obligatoria la documentación del fracaso del IBP antes del diagnóstico inicial o mediante documentación del fracaso del IBP en el momento de la selección. Se podrá hacer una preselección de los sujetos, pero no deberán otorgar su consentimiento, ni firmar un FCI, ni se les deberá ofrecer participar en FLUTE si no han cumplido los criterios diagnósticos de EE que exigen que hayan fracasado un ensayo de 8 semanas de IBP en altas dosis, EXCEPTO aquellos que hayan tomado IBP durante 8 semanas, que usarán la EGD en el estudio para esta documentación. El investigador y el posible sujeto deben tomar la decisión de completar un ensayo con IBP independientemente de cualquier consideración del estudio. No hay tiempo suficiente para realizar el ensayo de 8 semanas dentro del estudio actual. Si se obtuviera el consentimiento de un sujeto por error y la selección fracasa por este motivo, se podrá volver a seleccionar según se describe en el protocolo.
    4. Tener antecedentes comunicados por el sujeto de ≥3 episodios de disfagia (dificultad para tragar la comida) en los 7 días previos a la selección.
    5. Tener una puntuación global de síntomas de la EE en 7 días >3 al inicio (la puntuación de la EE debe permanecer >3 en las visitas 1, 2 y 3 previas a la aleatorización). Esta se realizará en papel durante la visita de selección.
    6. Estar dispuesto a cumplir las pautas de tratamiento, los procedimientos y el calendario de visitas relacionados con el estudio y ser capaz de ello.
    Antes de la aleatorización.
    7. Para determinar antes de la aleatorización: presentar indicios de EE, definidos como concentración máxima de eosinófilos ≥15/CGA. Para garantizar que se pueda efectuar un diagnóstico, se deberán tomar al menos 5-6 biopsias que incluyan muestras tanto proximales como distales (~3 de cada).
     No se aceptará ninguna EGD o biopsia realizada fuera de FLUTE para cumplir los criterios de idoneidad.
     Se podrán tomar y procesar biopsias opcionales de forma local para uso local, si se especifica en el FCI local.
     Las biopsias se deberán obtener ANTES de la evaluación de los síntomas iniciales de 4 semanas. La idoneidad desde una perspectiva histológica se basará únicamente en la evaluación del anatomopatólogo central.
    8. Para determinar antes de la aleatorización: en el diario, comunicar al menos 3 episodios de disfagia (dificultad para trabar la comida) en cada uno de los últimos 7 días durante los últimos 14 días de la evaluación de los síntomas iniciales de 4 semanas.
    9. Para determinar antes de la aleatorización: cumplimentación del diario al menos 5 de cada 7 días durante los últimos 14 días de la evaluación de los síntomas iniciales de 4 semanas.
    E.4Principal exclusion criteria
    Subjects will not be entered in FLUTE for any of the following reasons:
    Before entering 4-week Baseline Symptom Assessment
    1. Have known contraindication, hypersensitivity, or intolerance to corticosteroids;
    2. Have any physical, mental, or social condition or history of illness or laboratory abnormality that in the Investigator’s judgment might interfere with study procedures or the ability of the subject to adhere to and complete the study;
    3. Presence of oral or esophageal mucosal infection of any type;
    4. Have any mouth or dental condition that prevents normal eating;
    5. Have any condition affecting the esophageal mucosa or altering esophageal motility other than EoE, including erosive esophagitis (grade B or higher as per the Los Angeles Classification of Gastroesophageal Reflux Disease), hiatus hernia longer than 3 cm, Barrett’s esophagus, and achalasia;
    6. Use of systemic (oral or parenteral) corticosteroids within 60 days prior to Screening, use of inhaled/swallowed corticosteroids within 30 days prior to Screening, or extended use of high-potency dermal topical corticosteroids within 30 days prior to Screening;
    7. Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must remain stable after signing ICF);
    8. Morning (0700 to 0800 hours, or as close to that window as possible) serum cortisol level ≤5 µg/dL (138 nmol/L);
    9. Use of biologic immunomodulators in the 24 weeks prior to Screening;
    10. Use of calcineurin inhibitors or purine analogues (azathioprine, 6 mercaptopurine) in the 12 weeks prior to Screening;
    11. Use of potent cytochrome P450 (CYP) 3A4 inhibitors (e.g., ritonavir and ketoconazole) in the 12 weeks prior to Screening;
    12. Have a contraindication to or factors that substantially increase the risk of EGD or esophageal biopsy or have narrowing of the esophagus that precludes EGD with a standard 9 mm endoscope;
    13. Have history of an esophageal stricture requiring dilatation within the previous 12 weeks prior to Screening;
    14. Subjects who have initiated, discontinued or changed dosage regimen of PPIs, H2 antagonists, antacids or antihistamines for any condition such as GERD or allergic rhinitis within 4 weeks prior to qualifying endoscopy. These drugs must remain constant throughout the study.
    15. Infection with hepatitis B, hepatitis C, or human immunodeficiency virus (to be tested during Screening);
    • The following parameters will be utilized to determine hepatitis B and hepatitis C infection: positive for hepatitis B surface antigen [HBsAg], total hepatitis B core antibody [anti HBc], or hepatitis C virus antibody. Subjects who are positive for hepatitis B surface antibody, but negative for HBsAg and anti HBc, will be eligible.
    16. Have gastrointestinal (GI) bleeding within 4 weeks prior to Screening or between the Screening Visit and the Randomization Visit;
    17. Have current (>30 days) chronic infection, immunosuppression, or immunodeficiency;
    18. Have history or presence of Crohn’s disease, celiac disease, or other inflammatory disease of the GI tract, including eosinophilic gastroenteritis;
    19. Have current alcohol or drug abuse in the opinion of the Investigator;
    20. Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study;
    • Serum pregnancy test at Screening and urine pregnancy test during 4-week Baseline Symptom Assessment in women of childbearing potential must be negative.
    21. Sexually active females of childbearing potential who do not agree to follow highly effective contraceptive methods through the Follow up Visit;
    • For systemic contraceptive, use must be stable for ≥28 days prior to Screening.
    • Female subjects with surgical menopause or menopause confirmed by follicle stimulating hormone/luteinizing hormone do not require contraception or pregnancy testing during the study.
    22. Participation in a clinical study involving an investigational product within 30 days (or 5 half-lives, whichever is longer) of Screening;
    Before randomization
    23. A serum cortisol level <18 µg/dL (497 nmol/L) at 60 minutes with adrenocorticotropic hormone (ACTH) stimulation test using 250 µg cosyntropin (i.e., a positive result on the ACTH stimulation test).
    Los sujetos no podrán incluirse en FLUTE por cualquiera de los motivos que siguen:
    Antes de entrar en la evaluación de los síntomas iniciales de 4 semanas:
    1. Tener una contraindicación, hipersensibilidad o intolerancia a los corticosteroides conocida.
    2. Tener una afección física, mental o social, o antecedentes de enfermedad o anomalías analíticas que, a juicio del investigador, pudieran interferir en los procedimientos del estudio o la capacidad del sujeto para cumplir el estudio y completarlo.
    3. Presencia de infección de la mucosa bucal o esofágica de cualquier tipo.
    4. Tener cualquier afección bucal o dental que impida comer de forma normal.
    5. Tener cualquier afección que afecte la mucosa esofágica o altere la motilidad esofágica, aparte de la EE, incluida la esofaguitis erosiva (grado B o superior según la clasificación de Los Ángeles de la enfermedad por reflujo gastroesofágico), hernia de hiato de más de 3 cm, esófago de Barrett y acalasia.
    6. El uso de corticosteroides sistémicos (orales o parenterales) en el plazo de los 60 días previos a la selección, el uso de corticosteroides inhalados/tragados en el plazo de los 30 días previos a la selección o el uso extendido de corticosteroides tópicos dérmicos de alta potencia en el plazo de los 30 días previos a la selección.
    7. Inicio de una dieta de eliminación o dieta elemental en el plazo de los 30 días previos a la selección (la dieta debe continuar estable tras la firma del FCI).
    8. Concentración de cortisol en suero por la mañana (de las 07:00 a las 08:00 horas o los más cerca a dicho intervalo como sea posible) ≤5 μg/dl (138 nmol/l).
    9. Uso de inmunomoduladores biológicos en las 24 semanas previas a la selección.
    10. Uso de inhibidores de la calcineurina o análogos de la purina (azatioprina, 6-mercaptopurina) en las 12 semanas previas a la selección.
    11. Uso de inhibidores potentes del citocromo P450 (CYP) 3A4 (p. ej., ritonavir y ketoconazol) en las 12 semanas previas a la selección.
    12. Tener una contraindicación a la EGD o biopsia esofágica o factores que aumenten de forma sustancial el riesgo que conlleva, o padecer una estenosis esofágica que impida la EGD con un endoscopio estándar de 9 mm.
    13. Tener antecedentes de una estenosis esofágica que requiera dilatación en las 12 semanas previas a la selección.
    14. Sujetos que han iniciado, interrumpido o cambiado pautas posológicas de IBP, antagonistas H2, antiácidos o antihistamínicos por cualquier afección como la ERGE o la rinitis alérgica en las 4 semanas previas a la endoscopia de selección. Estos fármacos deben permanecer constantes durante todo el estudio.
    15. Infección por el virus de la hepatitis B, hepatitis C o virus de la inmunodeficiencia humana (se analizará durante la selección).
     Se usarán los siguientes parámetros para determinar la infección por hepatitis B y hepatitis C: positivo para el antígeno de superficie del virus de la hepatitis B [HBsAg], anticuerpos centrales totales contra el virus de la hepatitis B [anti-HBc] o anticuerpo contra el virus de la hepatitis C. Los sujetos que den positivo para el anticuerpo de superficie del virus de la hepatitis B, pero negativo para HBsAg y anti-HBc, serán aptos.
    16. Tener hemorragia gastrointestinal (GI) en el plazo de las 4 semanas previas a la selección o entre la visita de selección y la visita de aleatorización.
    17. Tener una infección, inmunodepresión o inmunodeficiencia crónica actual (>30 días).
    18. Tener antecedentes o presencia de enfermedad de Crohn, enfermedad celíaca u otra enfermedad inflamatoria del tubo digestivo, incluida la gastroenteritis eosinofílica.
    19. Padecer una drogadicción o alcoholismo en la actualidad en opinión del investigador.
    20. Sujetos de sexo femenino que estén embarazadas, en periodo de lactancia o planeen quedarse embarazadas durante el estudio.
     Las mujeres en edad fértil deben dar negativo en la prueba de embarazo en suero en la selección y en la prueba de embarazo en orina durante la evaluación de los síntomas iniciales de 4 semanas.
    21. Mujeres en edad fértil sexualmente activas que no acepten usar métodos anticonceptivos de alta eficacia hasta la visita de seguimiento.
     En el caso de los anticonceptivos sistémicos, su uso debe haber sido estable durante ≥28 días antes de la selección.
     Las mujeres con menopausia quirúrgica o menopausia confirmada mediante la hormona folículoestimulante/hormona luteinizante no necesitan usar métodos anticonceptivos ni someterse a las pruebas de embarazo durante el estudio.
    22. Participación en un estudio clínico con un producto en investigación en el plazo de los 30 días (o 5 semividas, lo que dure más) previos a la selección.
    E.5 End points
    E.5.1Primary end point(s)
    The following primary efficacy endpoint will be evaluated at Week 12 to assess
    EoE response:
    • Histology: percentage of subjects with a with ≤6 PEAK eosinophils/HPF after assessing at least 5-6 biopsies from the proximal and distal esophagus where the HPF area is 235 square microns (40 magnification lens with a 20 mm ocular).
    El siguiente criterio de valoración principal de la eficacia se evaluará en la semana 12 para evaluar la respuesta de la EE:
     Histología: porcentaje de sujetos con concentración máxima de eosinófilos ≤6/CGA tras evaluar al menos 5-6 biopsias del esófago proximal y distal (~3 de cada) en las que el área de CGA sea de 235 micras cuadradas (lente de 40 aumentos con un ocular de 22 mm).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    Semana 12
    E.5.2Secondary end point(s)
    The following secondary efficacy endpoints will be evaluated:
    • EoE sustained response: percentage of subjects who met the primary endpoint at Week 12 and maintained the primary endpoint at Week 26 and Week 52;
    • Change from baseline EREFs at Week 12, Week 26, and Week 52;
    • Endoscopic changes will as per the EREFs evaluation based on the following endoscopic features: edema, rings, exudates, furrows, stricture, and several miscellaneous features (crepe paper esophagus, narrow caliber esophagus, and esophageal erosions).
    • Percentage of subjects with a peak eosinophils/HPF number <1 and <15 at Week 12, Week 26, and Week 52;
    • Change from baseline Global EoE Symptom Score assessed prior to randomization, which will be assessed for the 7 day period prior to the following study visits: Week 4, Week 8, Week 12, Week 14, Week 18, Week 22, Week 26, Week 28, Week 36, Week 44, and Week 52;
    • Dysphagia: Change in the number of dysphagia episodes at baseline (14-day period prior to randomization) compared with the 14-day period prior to the time point of interest (Week 12, Week 26 and Week 52);
    • Change from baseline 7-day EEsAI total score assessed prior to randomization to those assessed at Week 12, Week 26, and Week 52;
    • Change from baseline 7-day EEsAI subscores to those assessed at Week 12, Week 26, and Week 52;
    • Percentage of subjects with mean 7-day EEsAI total score <20 to those assessed at Week 12, Week 26, and Week 52;
    • Change from baseline PGIS assessed prior to randomization to those assessed at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44 and 52;
    • PGIC at weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52.
    • Assessment of treatment failure and relapse, including:
    • Percentage of histologic non-responders by dose at Week 12, Week 26, and Week 52;
    • Percentage of subjects requiring emergency endoscopic food disimpaction by dose before Week 14, between Week 14 and Week 28, and between Week 28 and Week 52;
    • Percentage of subjects requiring esophageal dilation by dosing group and part of the study
    se evaluarán los siguientes criterios de valoración secundarios de la eficacia:
     Respuesta mantenida de la EE: porcentaje de sujetos que cumplan el criterio de valoración principal en la semana 12 y mantengan el criterio de valoración principal en la semana 26 y semana 52.
     El cambio con respecto al inicio en la EREFs en la semana 12, semana 26 y semana 52.
     Los cambios endoscópicos se determinarán según la evaluación mediante la EREFs basada en los siguientes características endoscópicas: edema, anillos, exudados, surcos, estenosis y diversas características (esófago con aspecto de papel crepé, esófago de calibre estrecho y erosiones esofágicas).
     Porcentaje de sujetos con una cifra máxima de eosinófilos/CGA <1 y <15 en la semana 12, semana 26 y semana 52.
    Cambio con respecto al inicio en la puntuación global de síntomas de la EE, evaluada antes de la aleatorización, para el periodo de 7 días antes de las siguientes visitas del estudio: semana 4, semana 8, semana 12, semana 14, semana 18, semana 22, semana 26, semana 28, semana 36, semana 44 y semana 52.
     Disfagia: cambio en el número de episodios de disfagia al inicio (periodo de 14 días previo a la aleatorización) comparado con el periodo de 14 días previo al punto temporal de interés (semanas 12, 26 y 52).
     Cambio con respecto al inicio en la puntuación total EEsAI de 7 días, evaluada antes de la aleatorización, hasta las evaluadas en la semana 12, semana 26 y semana 52.
     Cambio con respecto al inicio en las subpuntuaciones EEsAI de 7 días hasta las evaluadas en la semana 12, semana 26 y semana 52.
     Porcentaje de sujetos con una puntuación total EEsAI media de 7 días <20 de las evaluadas en la semana 12, semana 26 y semana 52.
     Cambio con respecto al inicio en la PGIS evaluada antes de la aleatorización hasta las evaluadas en la semanas 4, 8, 12, 14, 18, 22, 26, 28, 36, 44 y 52.
     PGIC en las semanas 4, 8, 12, 14, 18, 22, 26, 28, 36, 44 y 52.
     Evaluación del fracaso del tratamiento y la recaída, incluidos:
     Porcentaje de pacientes sin respuesta histológica por dosis en la semana 12, semana 26 y semana 52.
     Porcentaje de sujetos que necesiten de desimpactación alimentaria mediante endoscopia de urgencia por dosis antes de la semana 14, entre la semana 14 y la semana 28, y entre la semana 28 y la semana 52.
     Porcentaje de sujetos que necesiten de dilatación esofágica por grupo de dosis y parte del estudio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 12, Week 26, Week 52
    Semana 12, Semana 26, 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 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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.2.4Number of treatment arms in the trial5
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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
    Belgium
    Canada
    Germany
    Spain
    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
    LVLS
    UVUP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 95
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 23
    F.4.2.2In the whole clinical trial 100
    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
    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 Decision2017-09-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-10-23
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