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    Summary
    EudraCT Number:2018-003528-35
    Sponsor's Protocol Code Number:2693-CL-0301
    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:2019-07-05
    Trial 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 number2018-003528-35
    A.3Full title of the trial
    A Phase 3, Randomized, Placebo-controlled, 12-week Double-blind Study, followed by a Non-Controlled Extension Treatment Period, to Assess the Efficacy and Safety of Fezolinetant in Women Suffering from Moderate to Severe Vasomotor Symptoms (Hot Flashes) Associated with Menopause
    Estudio de fase III, aleatorizado, controlado con placebo, con enmascaramiento doble de 12 semanas, seguido de un periodo no controlado de prolongación del tratamiento con el fin de evaluar la eficacia y la seguridad de fezolinetant en mujeres con síntomas vasomotores (sofocos) de intensidad moderada a grave asociados a la menopausia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trial to Assess the Efficacy and Safety of Fezolinetant in Women Suffering from Moderate to Severe Hot Flashes Associated with Menopause
    Ensayo para evaluar la seguridad y eficacia de fezolinetant en mujeres que sufren sofocos de intensidad moderada a grave asociados a la menopausia.
    A.3.2Name or abbreviated title of the trial where available
    Skylight 1
    A.4.1Sponsor's protocol code number2693-CL-0301
    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 SponsorAstellas Pharma Global Development, 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 supportAstellas Pharma Global Development, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstellas Pharma Europe B.V. – Global Development Operations
    B.5.2Functional name of contact pointService Desk
    B.5.3 Address:
    B.5.3.1Street AddressSylviusweg 62
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 BE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031071 545 5878
    B.5.5Fax number0031071 545 5224
    B.5.6E-mailctu@astellas.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 nameFezolinetant
    D.3.2Product code ESN364
    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 INNFEZOLINETANT
    D.3.9.1CAS number 1629229-37-3
    D.3.9.2Current sponsor codeESN364
    D.3.9.4EV Substance CodeSUB188609
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 nameFezolinetant
    D.3.2Product code ESN364
    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 INNFEZOLINETANT
    D.3.9.1CAS number 1629229-37-3
    D.3.9.2Current sponsor codeESN364
    D.3.9.4EV Substance CodeSUB188609
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    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
    Moderate to Severe Vasomotor Symptoms (Hot Flashes) Associated with Menopause
    Síntomas vasomotores (sofocos) de intensidad moderada a grave asociados a la menopausia
    E.1.1.1Medical condition in easily understood language
    Hot Flashes Associated with Menopause
    Sofocos asociados a la menopausia
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10020407
    E.1.2Term Hot flashes
    E.1.2System Organ Class 100000004866
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of moderate to severe vasomotor symptoms (VMS).
    ● The estimand of the primary objective will use a hypothetical strategy and compare patients as though they had continued on the assigned treatment.
    Evaluar la eficacia de fezolinetant en comparación con un placebo en cuanto a la frecuencia y la intensidad de los síntomas vasomotores (SVM) entre moderados y leves.
    ● El estimando del objetivo principal usará una estrategia hipotética y comparará a las pacientes como si hubiesen continuado con el tratamiento asignado.
    E.2.2Secondary objectives of the trial
    Key secondary objective:
    ● To evaluate the efficacy of fezolinetant versus placebo on patient-reported sleep disturbance.
    Secondary objectives:
    ● To evaluate the effect of fezolinetant versus placebo on the frequency and severity of moderate to severe VMS at weekly time points.
    ● To evaluate the safety and tolerability of fezolinetant.
    Objetivo secundario fundamental:
    ● Evaluar la eficacia de fezolinetant en comparación con un placebo en cuanto a la alteración del sueño percibida por las pacientes.
    Objetivos secundarios:
    ● Evaluar el efecto de fezolinetant en comparación con un placebo en cuanto a la frecuencia y la intensidad de los SVM entre moderados y graves en puntos temporales semanales.
    ● Evaluar la seguridad y la tolerabilidad de fezolinetant.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent and privacy language as per national regulations must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
    2. Subject is born female, aged ≥40 years and ≤65 years of age at the screening visit.
    3. Subject has a body mass index ≥ 18 kg/m2 and ≤ 38 kg/m2.
    4. Subject must be seeking treatment or relief for VMS associated with menopause and
    confirmed as menopausal per 1 of the following criteria at the screening visit:
    ● Spontaneous amenorrhea for ≥ 12 consecutive months
    ● Spontaneous amenorrhea for ≥6 months with biochemical criteria of menopause (FSH > 40 IU/L); or
    ● Having had bilateral oophorectomy ≥ 6 weeks prior to the screening visit (with or without hysterectomy).
    5. Within the 10 days prior to randomization, subject must have a minimum average of 7 to 8 moderate to severe HFs (VMS) per day, or 50 to 60 per week.
    6. Subject is in good general health as determined on the basis of medical history and general physical examination, including a bimanual clinical pelvic examination and clinical breast examination devoid of relevant clinical findings, performed at the screening visit; hematology and biochemistry parameters, pulse rate and/or blood pressure and ECG within the reference range for the population studied, or showing no clinically relevant deviations, as judged by the investigator.
    7. Subject has documentation of a normal/negative or no clinically significant findings mammogram (obtained at screening or within the prior 12 months of study enrollment). Appropriate documentation includes a written report or an electronic report indicating normal/negative or no clinically significant mammographic findings.
    8. Subject is willing to undergo a TVU to evaluate the uterus and ovaries at screening and at week 52 (EOT), and for subjects who are withdrawn from the study prior to completion, a TVU at the ED visit. This is not required for subjects who have had a partial (supra-cervical) or full hysterectomy.
    9. Subject is willing to undergo an endometrial biopsy at screening and at week 52 (EOT), for subjects with uterine bleeding, and for subjects who are withdrawn from the study prior to completion. This is not required for subjects who have had a partial (supracervical) or full hysterectomy.
    10. Subject has documentation of a normal or not clinically significant Pap test (or equivalent cervical cytology) in the opinion of the investigator within the previous 9 months or at screening.
    11. Subject has a negative urine pregnancy test at screening.
    12. Subject has a negative serology panel (i.e., negative hepatitis B surface antigen, negative hepatitis C virus antibody and negative human immunodeficiency virus antibody screens) at screening.
    13. Subject agrees not to participate in another interventional study while participating in the present study.
    1. La paciente o su representante legal autorizado facilitarán el consentimiento informado y el texto sobre privacidad por escrito, aprobado por el Comité de Ética independiente (CEI) conforme a la normativa, antes de que se realice cualquier procedimiento relacionado con el estudio (incluida la retirada de medicación prohibida, si procede).
    2. La paciente es mujer, de ≥40 y ≤65 años en la visita de selección.
    3. La paciente cuenta con un índice de masa corporal ≥18 kg/m2 y ≤38 kg/m2.
    4. La paciente busca tratamiento o alivio para los SVM derivados de la menopausia y tiene menopausia confirmada mediante uno de los siguientes criterios en la visita de selección:
    ● amenorrea espontánea durante ≥12 meses consecutivos
    ● amenorrea espontánea durante ≥6 meses con criterios bioquímicos de menopausia (FSH >40 UI/l); o
    ● haberse sometido a una ovariectomía bilateral ≥6 semanas antes de la visita de selección (con o sin histerectomía).
    5. En los 10 días previos a la aleatorización, la paciente deberá presentar una media mínima diaria de 7 a 8 sofocos (SVM) de intensidad moderada a grave o de 50 a 60 a la semana.
    6. La paciente presenta un buen estado de salud general, determinado mediante su historia médica y la exploración física general, incluidas una exploración pélvica clínica bimanual y una exploración clínica de mama libres de hallazgos clínicos relevantes realizadas en la visita de selección, parámetros de hematología y bioquímica, pulso o tensión arterial y ECG dentro de los intervalos de referencia para la población estudiada o sin desviaciones clínicamente relevantes en opinión del investigador.
    7. La paciente cuenta con documentación de una mamografía normal/negativa o sin hallazgos clínicamente significativos (obtenida en la selección o en los 12 meses anteriores a la inscripción en el estudio). Para ser considerada adecuada, la documentación debe incluir un informe por escrito o electrónico que indique que la mamografía es normal/negativa o que no presenta hallazgos clínicamente significativos.
    8. La paciente está dispuesta a someterse a una ETV para evaluar el útero y los ovarios en la selección y en la semana 52 (FdT) y, en el caso de las pacientes retiradas del estudio antes de la finalización, se hará una ETV en la visita de SA. Esto no será necesario en el caso de las pacientes que se hayan sometido a una histerectomía parcial (supracervical) o total.
    9. La paciente está dispuesta a someterse a una biopsia de endometrio en la selección y en la semana 52 (FdT) en el caso de las pacientes con hemorragia uterina o retiradas del estudio antes de su finalización. Esto no será necesario en el caso de las pacientes que se hayan sometido a una histerectomía parcial (supracervical) o total.
    10. La paciente cuenta con documentación de una prueba de Papanicolau normal o no clínicamente significativa (o citología cervical equivalente), en opinión del investigador, realizada en los 9 meses anteriores o en la selección.
    11. La paciente ha obtenido un resultado negativo en una prueba de embarazo en orina realizada en la selección.
    12. La paciente cuenta con un perfil de serología negativo (es decir, antígeno de superficie virus de la hepatitis B negativo, anticuerpo del virus de la hepatitis C negativo y anticuerpo del virus de la inmunodeficiencia humana negativo) en la selección.
    13. La paciente acepta no participar en otro estudio intervencionista mientras participe en este estudio.
    E.4Principal exclusion criteria
    1. Subject uses a prohibited therapy (strong or moderate CYP1A2 inhibitors, HRT, hormonal contraceptive or any treatment for VMS [prescription, over the counter or herbal]) or is not willing to wash out and discontinue use of such drugs for the full duration of study conduct.
    2. Subject has known substance abuse or alcohol addiction within 6 months of screening, as assessed by the investigator.
    3. Subject has previous or current history of a malignant tumor, except for basal cell carcinoma.
    4. Subject has hypertension defined as systolic blood pressure ≥ 130 mmHg or diastolic blood pressure as ≥ 80 mmHg based on an average of 2 to 3 readings at screening and randomization. Subjects with a medical history with hypertension who are well controlled may be enrolled at the discretion of the investigator.
    5. Subject has history of severe allergy, hypersensitivity or intolerance to drugs in general, including the study drug and any of its excipients.
    6. For subjects with a uterus: Subject has an unacceptable result from the TVU assessment at screening (i.e., full length of endometrial cavity cannot be visualized or presence of a clinically significant finding).
    7. For subjects with a uterus: Subject has an endometrial biopsy confirming presence of disordered proliferative endometrium, endometrial hyperplasia, endometrial cancer or other clinically significant findings in the opinion of the investigator at screening. A biopsy with insufficient material for evaluation, or unevaluable material, is acceptable provided the endometrial thickness is less than 4 mm.
    8. Subject has a history within the last 6 months of undiagnosed uterine bleeding.
    9. Subject has a history of seizures or other convulsive disorders.
    10. Subject has a medical condition or chronic disease (including history of neurological [including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [e.g., moderate asthma], endocrine or gynecological disease) or malignancy that could confound interpretation of the study outcome in the opinion of the investigator.
    11. Subject has active liver disease, jaundice, elevated liver aminotransferases (ALT or AST), elevated total or direct bilirubin, elevated INR, or elevated alkaline phosphatase (ALP). Patients with mildly elevated ALT or AST up to <1.5 times the upper limit of normal (ULN) can be enrolled if total and direct bilirubin are normal. Patients with mildly elevated ALP (up to <1.5 x ULN) can be enrolled if cholestatic liver disease is excluded and no cause other than fatty liver is diagnosed. Patients with Gilbert’s syndrome with elevated total bilirubin may be enrolled as long as direct bilirubin, hemoglobin, and reticulocytes are normal.
    12. Subject has creatinine > 1.5 × ULN; or estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula < 59 mL/min per 1.73 m2 at screening.
    13. Subject has a history of suicide attempt or suicidal behavior within the last 12 months or has suicidal ideation within the last 12 months (a response of “yes” to question 4 or 5 on the suicidal ideation portion of the Columbia Suicide Severity Rating Scale [C-SSRS]), or who is at significant risk to commit suicide, as assessed by the investigator at screening and at visit 2 (randomization).
    14. Subject has had previous exposure with fezolinetant.
    15. Subject is participating concurrently in another interventional study or participated in an interventional study within 28 days prior to screening, or received any investigational drug within 28 days or within 5 half-lives prior to screening, whichever is longer.
    1. La paciente usa un tratamiento prohibido (inhibidores potentes o moderados del CYP1A2, TRH, anticonceptivos hormonales o algún tratamiento para los SVM [con o sin receta o fitoterapia]) o no accede a un periodo de reposo farmacológico y a suspender el uso de dichos fármacos durante la realización del estudio.
    2. La paciente ha abusado de sustancias estupefacientes o del alcohol en los 6 meses anteriores a la selección, según evaluación del investigador.
    3. La paciente tiene antecedentes o sufre actualmente una neoplasia maligna, excepto el carcinoma basocelular.
    4. La paciente padece hipertensión, definida como tensión arterial sistólica ≥130 mmHg o diastólica ≥80 mmHg según una media de 2 o 3 lecturas en la selección y la aleatorización. Las pacientes con antecedentes médicos de hipertensión bien controlada podrán participar a discreción del investigador.
    5. La paciente tiene antecedentes de alergia grave, hipersensibilidad o intolerancia a los fármacos en general, incluido el fármaco del estudio y sus excipientes.
    6. Para pacientes con útero: la paciente presenta un resultado inaceptable en la ETV en la selección (es decir, no se puede ver la totalidad de la cavidad endometrial o hay un hallazgo clínicamente significativo).
    7. Para pacientes con útero: la paciente presenta en la selección un resultado de una biopsia de endometrio que confirma la presencia de endometrio proliferativo desordenado, hiperplasia de endometrio, cáncer de endometrio u otros hallazgos clínicamente significativos en opinión del investigador. Se aceptará una biopsia con material insuficiente para la evaluación o material no evaluable siempre que el grosor del endometrio sea inferior a 4 mm.
    8. La paciente presenta antecedentes en los 6 meses anteriores de hemorragia uterina no diagnosticada.
    9. La paciente tiene antecedentes de epilepsia u otros trastornos convulsivos.
    10. La paciente padece una afección o enfermedad crónica (incluidos trastornos neurológicos —y cognitivos—, hepáticos, renales, cardiovasculares, digestivos, pulmonares —como asma moderada—, endocrinos y ginecológicos) o una neoplasia que, en opinión del investigador, podría confundir la interpretación de los resultados.
    11. La paciente padece una hepatopatía activa, ictericia o aminotransferasas hepáticas elevadas (ALT o AST), bilirrubina total o directa elevada, CIN elevado o fosfatasa alcalina (FA) elevada. Las pacientes con ALT o AST ligeramente elevadas, hasta >1,5 veces el límite superior de la normalidad (LSN), podrán participar si la bilirrubina total y directa son normales. Las pacientes con FA ligeramente elevada (hasta <1,5 el LSN) podrán participar si la hepatopatía colestásica queda excluida y no se diagnostica otra causa que no sea el hígado graso. Las pacientes con síndrome de Gilbert y bilirrubina total elevada podrán participar siempre que la bilirrubina directa, la hemoglobina y los reticulocitos sean normales.
    12. La paciente presenta un nivel de creatinina >1,5 el LSN o una filtración glomerular estimada (FGe) según la fórmula de la modificación de la dieta en las nefropatías <59 ml/min por cada 1,73 m2 en la selección.
    13. La paciente tiene antecedentes de intento de suicidio o conducta suicida en los últimos 12 meses o ha tenido ideas suicidas en los últimos 12 meses (una respuesta afirmativa en la pregunta 4 o 5 de la parte de ideas suicidas de la Escala de Columbia para evaluar la intensidad de la ideación suicida [C-SSRS]) o presenta un riesgo considerable de suicidarse, según evaluación del investigador en la selección y en la visita 2 (aleatorización).
    14. La paciente ha estado expuesta anteriormente a fezolinetant.
    15. La paciente está participando al mismo tiempo en otro estudio intervencionista o ha participado en un estudio intervencionista en los 28 días anteriores a la selección, o ha recibido un fármaco en fase de investigación en los 28 días o 5 semividas anteriores a la selección, el período que sea más largo.
    E.5 End points
    E.5.1Primary end point(s)
    Co-primary:
    ● Mean change in the frequency of moderate to severe VMS from baseline to week 4
    ● Mean change in the frequency of moderate to severe VMS from baseline to week 12
    ● Mean change in the severity of moderate to severe VMS from baseline to week 4
    ● Mean change in the severity of moderate to severe VMS from baseline to week 12
    Variables coprincipales:
    ● Cambio medio en la frecuencia de los SVM de intensidad moderada a grave entre el periodo inicial y la semana 4.
    ● Cambio medio en la frecuencia de los SVM de intensidad moderada a grave entre el periodo inicial y la semana 12.
    ● Cambio medio en la intensidad de los SVM moderados a graves entre el periodo inicial y la semana 4.
    ● Cambio medio en la intensidad de los SVM moderados a graves entre el periodo inicial y la semana 12.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Co-primary:
    ● Mean change in the frequency of moderate to severe VMS from baseline to week 4
    ● Mean change in the frequency of moderate to severe VMS from baseline to week 12
    ● Mean change in the severity of moderate to severe VMS from baseline to week 4
    ● Mean change in the severity of moderate to severe VMS from baseline to week 12
    Variables coprincipales:
    ● Cambio medio en la frecuencia de los SVM de intensidad moderada a grave entre el periodo inicial y la semana 4.
    ● Cambio medio en la frecuencia de los SVM de intensidad moderada a grave entre el periodo inicial y la semana 12.
    ● Cambio medio en la intensidad de los SVM moderados a graves entre el periodo inicial y la semana 4.
    ● Cambio medio en la intensidad de los SVM moderados a graves entre el periodo inicial y la semana 12.
    E.5.2Secondary end point(s)
    Key Secondary:
    ● Mean change in the Patient-reported Outcomes Measurement Information System Sleep Disturbance – Short Form 8b (PROMIS SD SF 8b) Total Score from baseline to week 12
    Secondary:
    ● Mean change in the frequency of moderate and severe VMS from baseline to each week up to week 12
    ● Mean change in the severity of moderate and severe VMS from baseline to each week up to week 12
    ● Mean percent reduction in the frequency of moderate and severe VMS from baseline to each week up to week 12
    ● Percent reduction ≥ 50% and at 100% in the frequency of moderate and severe VMS from baseline to each week up to week 12
    ● Mean change in the frequency of moderate to severe VMS from baseline to week 24 (descriptive)
    ● Mean change in the severity of moderate to severe VMS from baseline to week 24 (descriptive)
    Variable secundaria fundamental:
    ● Cambio medio en la puntuación total entre el periodo inicial y la semana 12 en el Sistema de información de medición de resultados percibidos por los pacientes sobre alteración del sueño – Cuestionario breve 8b (PROMIS SD SF 8b).
    Variables secundarias:
    ● Cambio medio en la frecuencia de los SVM de intensidad .moderada y grave entre el periodo inicial y cada semana hasta la semana 12.
    ● Cambio medio en la intensidad de los SVM moderados y graves entre el periodo inicial y cada semana hasta la semana 12.
    ● Reducción porcentual media en la frecuencia de los SVM de intensidad moderada y grave entre el periodo inicial y cada semana hasta la semana 12.
    ● Reducción porcentual ≥50 % y del 100 % en la frecuencia de los SVM de intensidad moderada y grave entre el periodo inicial y cada semana hasta la semana 12.
    ● Cambio medio en la frecuencia de los SVM de intensidad .moderada a grave entre el periodo inicial y la semana 24 (descriptivo)
    ● Cambio medio en la intensidad de los SVM moderados a graves entre el periodo inicial y la semana 24 (descriptivo).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary:
    ● Mean change in the frequency of moderate and severe VMS from baseline to each week up to week 12
    ● Mean change in the severity of moderate and severe VMS from baseline to each week up to week 12
    ● Mean percent reduction in the frequency of moderate and severe VMS from baseline to each week up to week 12
    ● Percent reduction ≥ 50% and at 100% in the frequency of moderate and severe VMS from baseline to each week up to week 12
    ● Mean change in the frequency of moderate to severe VMS from baseline to week 24 (descriptive)
    ● Mean change in the severity of moderate to severe VMS from baseline to week 24 (descriptive)
    Variable secundaria fundamental: Cambio medio en la puntuación total entre el periodo inicial y la semana 12 en el Sistema de información de medición de resultados percibidos por los pacientes sobre alteración del sueño – Cuestionario breve 8b (PROMIS SD SF 8b). Variables secundarias: Cambio medio en la frecuencia de los SVM de intensidad .moderada y grave entre el periodo inicial y cada semana hasta la semana 12. Cambio medio en la intensidad de los SVM moderados y graves entre el periodo inicial y cada semana hasta la semana 12. Reducción porcentual media en la frecuencia de los SVM de intensidad moderada y grave entre el periodo inicial y cada semana hasta la semana 12. (por falta de espacio revisar E.5.2 en inglés)
    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 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) 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 Yes
    E.8.1.7.1Other trial design description
    Todos los sujetos recibirán el tratamiento activo después de 12 semanas de tratamiento
    After 12 weeks of treatment, all subjects will receive active treatment.
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    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
    Canada
    Czech Republic
    Germany
    Hungary
    Poland
    Romania
    Spain
    Ukraine
    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
    LVLS
    Ultima visita del último sujeto
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 450
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 86
    F.4.2.2In the whole clinical trial 450
    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
    Ninguno
    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 Decision2019-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-10
    P. End of Trial
    P.End of Trial StatusOngoing
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