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    Summary
    EudraCT Number:2016-001767-37
    Sponsor's Protocol Code Number:178-CL-204
    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:2021-02-17
    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 number2016-001767-37
    A.3Full title of the trial
    A Phase 3, Double blind, Randomized, Multicenter, Parallel Group, Placebo controlled Sequential Dose Titration Study to Evaluate Efficacy, Safety and Pharmacokinetics of Mirabegron in Pediatric Subjects from 5 to < 18 Years of Age with Overactive Bladder
    Estudio de fase 3 de ajuste de dosis secuencial, controlado con placebo, de doble enmascaramiento, aleatorizado, multicéntrico y de grupo paralelo para evaluar la eficacia, la seguridad y la farmacocinética de mirabegrón en sujetos pediátricos de 5 a <18 años de edad con vejiga hiperactiva
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate how effective and safe the study medication 'mirabegron' is and how long it stays in the body in children aged 5 to less than 18 years with symptoms of an overactive bladder
    Estudio para investigar la efectividad y seguridad del medicamento "mirabegron" y cuánto tiempo permanece en el organismo de niños de 5 a menos de 18 años de edad con síntomas de vegija hiperactiva.
    A.3.2Name or abbreviated title of the trial where available
    Dolphin Study
    A.4.1Sponsor's protocol code number178-CL-204
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/350/2019
    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 number31715455050
    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 Yes
    D.2.1.1.1Trade name Betmiga
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameMirabegron
    D.3.4Pharmaceutical form Prolonged-release 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 INNMIRABEGRON
    D.3.9.1CAS number 223673-61-8
    D.3.9.3Other descriptive nameMIRABEGRON
    D.3.9.4EV Substance CodeSUB32690
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 Yes
    D.2.1.1.1Trade name Betmiga
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameMirabegron
    D.3.4Pharmaceutical form Prolonged-release 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 INNMIRABEGRON
    D.3.9.1CAS number 223673-61-8
    D.3.9.3Other descriptive nameMIRABEGRON
    D.3.9.4EV Substance CodeSUB32690
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 namemirabegron
    D.3.2Product code YM178
    D.3.4Pharmaceutical form Granules for oral suspension
    D.3.4.1Specific paediatric formulation Yes
    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 INNMIRABEGRON
    D.3.9.1CAS number 223673-61-8
    D.3.9.2Current sponsor codeYM178
    D.3.9.3Other descriptive nameMIRABEGRON
    D.3.9.4EV Substance CodeSUB32690
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    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 placeboGranules for oral suspension
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    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
    Overactive bladder (OAB)
    Vejiga hiperactiva (VH)
    E.1.1.1Medical condition in easily understood language
    a sudden and uncontrollable urge to urinate (urinary incontinence)
    Urgencia para orinar repentina e incontrolable (incontinencia uirinaria)
    E.1.1.2Therapeutic area Body processes [G] - Biological Phenomena [G16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level LLT
    E.1.2Classification code 10059617
    E.1.2Term Overactive bladder
    E.1.2System Organ Class 100000004857
    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 mirabegron in children (5 to < 12 years of age) with OAB
    Evaluar la eficacia de mirabegrón en niños (de 5 a <12 años) con VH
    E.2.2Secondary objectives of the trial
    ● To evaluate the efficacy of mirabegron in children (5 to < 12 years of age) with OAB
    ● To evaluate the safety and tolerability of mirabegron in pediatric subjects with OAB
    ● To evaluate the pharmacokinetics after multiple dose administration of mirabegron in pediatric subjects with OAB
    - Evaluar la eficacia de mirabegrón en niños (de 5 a <12 años) con VH
    - Evaluar la seguridad y la tolerabilidad de mirabegrón en sujetos pediátricos con VH
    - Evaluar la farmacocinética tras la administración de varias dosis de mirabegrón en sujetos pediátricos con VH
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion at Visit 1/Week -4 (Screening)
    2. Subject has OAB defined according to the ICCS criteria.
    4. Subject weighs at least 13 kg at screening.
    5. Subject is able to take the IP in accordance with the protocol.
    6. Subject agrees to drink an adequate fluid volume during urine collection weekends, as instructed by the investigator.
    7. Subject and subject’s parent(s)/legal guardian(s) agree that the subject will not participate in another interventional study while participating in the present study.
    8. Subject and subject’s parent(s)/legal guardian(s) are willing and able to comply with the study requirements and with the concomitant medication restrictions.
    9. At least 1 of the following conditions apply:
    a. Not a female of childbearing potential (WOCBP)
    b. Female of childbearing potential who agrees to follow the contraceptive guidance from the time of informed consent/assent through at least 30 days after final IP administration.
    10. Female subject must agree not to breastfeed starting at screening and throughout the study period and for 30 days after final IP administration.
    11. Female subject must not donate ova starting at first dose of IP and throughout the study period and for 30 days after final IP administration.
    12. Male subject with female partner(s) of childbearing potential (including breastfeeding partner[s]) must agree to use contraception throughout the treatment period and for 30 days after final IP administration.
    13. Male subject must agree not to donate sperm during the treatment period and for 30 days after final IP administration.
    14. Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 30 days after final IP administration.

    Additional Inclusion at Visit 3/Week 0 (Baseline)
    15. Subject must have a micturition frequency of at least 8 times (on average) per day, in the 7 days prior to visit 3/week 0 (baseline), as recorded in the bladder e-diary.
    16. Subject must have at least 1 daytime incontinence episode (on average) per day, during the 7-day period before visit 3/baseline, as recorded in the bladder e-diary.
    17. Subject whose symptoms are not satisfactorily controlled with urotherapy and still fulfills the inclusion/exclusion criteria will enter the study.
    Inclusión en la visita 1/semana -4 (selección)
    2. El sujeto padece VH definida según los criterios de la ICCS.
    4. El sujeto pesa al menos 13 kg en la fase de selección.
    5. El sujeto puede tomar el PEI de acuerdo con el protocolo.
    6. El sujeto acepta beber un volumen adecuado de líquido durante los fines de semana de recogida de orina, según las instrucciones del investigador.
    7. Los padres/tutores legales del sujeto y el sujeto aceptan que el sujeto no participará en otro estudio de intervención mientras participe en el presente estudio.
    8. Los padres/tutores legales del sujeto y el sujeto están dispuestos y son capaces de cumplir los requisitos del estudio y las restricciones relativas a la medicación concomitante.
    9. La sujeto de sexo femenino no está embarazada (consulte el [Apéndice 12.3 Requisitos de anticoncepción]) y se da al menos una de las siguientes condiciones:
    a. No se trata de una mujer en edad fértil (consulte el [Apéndice 12.3 Requisitos de anticoncepción]).
    b. La mujer en edad fértil acepta seguir la guía anticonceptiva (consulte el [Apéndice 12.3 Requisitos de anticoncepción]) desde el momento en que se firme el asentimiento/consentimiento informado hasta al menos 30 días tras la administración final del PEI.
    10. Los sujetos de sexo femenino deben aceptar no amamantar a partir de la fase de selección, durante el periodo del estudio ni durante 30 días tras la administración final del PEI.
    11. Los sujetos de sexo femenino no deben donar óvulos desde la primera dosis del PEI, durante el periodo del estudio ni durante 30 días tras la administración final del PEI.
    12. Los sujetos masculinos con pareja, o parejas, femeninas en edad fértil (incluidas pareja, o parejas, que estén amamantando) deben aceptar el uso de un método anticonceptivo (consulte el [Apéndice 12.3 Requisitos de anticoncepción]) durante el periodo de tratamiento y 30 días tras la administración final del PEI.
    13. El sujeto masculino debe aceptar que no puede donar esperma durante el periodo de tratamiento ni 30 días tras la administración final del PEI.
    14. Los sujetos masculinos con pareja, o parejas, embarazadas deben aceptar practicar la abstinencia sexual o utilizar preservativo durante la duración del embarazo en el periodo del estudio y durante 30 días tras la administración final del PEI.
    Inclusión adicional en la visita 3/semana 0 (inicio del estudio)
    15. El sujeto debe tener una frecuencia de la micción de al menos 8 veces (de promedio) al día, en los 7 días anteriores a la visita 3/semana 0 (inicio del estudio), tal como se ha registrado en el diario electrónico sobre los hábitos de micción.
    16. El sujeto debe tener al menos un episodio diurno de incontinencia (de promedio) al día durante el periodo de 7 días anterior a la visita 3/inicio del estudio, tal como se ha registrado en el diario electrónico sobre los hábitos de micción.
    17. Los sujetos cuyos síntomas no se hayan controlado satisfactoriamente con la terapia urológica conductual y que sigan cumpliendo los criterios de inclusión/exclusión participarán en el estudio.
    E.4Principal exclusion criteria
    Exclusion at Visit 1/Week -4 (Screening)
    1. Subject has extraordinary daytime only urinary frequency according to the ICCS definition
    ● This applies to a toilet-trained child who has the frequent need to void that is associated with small micturition volumes solely during the day
    ● The daytime voiding frequency is at least once per hour with an average voided volume of < 50% of expected bladder capacity (EBC) (typically 10% to 15%)
    ● Incontinence is rare and nocturia is absent
    Subject has
    2. an uroflow indicative of pathology other than OAB
    3. monosymptomatic enuresis
    4. dysfunctional voiding
    5. bladder outlet obstruction, except if successfully treated
    6. anatomical anomalies (surgically treated or untreated) that affect lower urinary tract function
    7. Subject with hematuria on dipstick test. In the case of hematuria on dipstick test in a female during menstruation, the test can be repeated before randomization (after the end of menstruation)
    8. Subject with diabetes insipidus
    Subject has
    9. kidney or bladder stones
    10. suffered from chronic UTI or has had more than 3 UTIs in the 2 months prior to visit 1/week -4 (screening)
    11. removed
    12. stage 2 hypertension or subject has stage 1 hypertension that is not well controlled, as defined by the 2017 American Academy of Pediatrics Clinical Practice Guidelines
    13. QTcF > 440 msec on screening ECG, a risk of QT prolongation (e.g., hypokalemia, long QT syndrome [LQTS] or family history of LQTS or exercise-induced syncope) or is currently taking medication known to prolong the QT interval
    14. Subject’s aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is ≥ 2 × upper limit of normal (ULN) or total bilirubin (TBL) is ≥ 1.5 × ULN according to age and sex (subjects with Gilbert’s syndrome are excepted from the bilirubin threshold)
    Subject has
    15. mild or moderate renal impairment (estimated glomerular filtration rate according to the modified Schwartz of < 60 mL/min per 1.73 m2)
    16. a symptomatic (symptoms can include pain, fever, hematuria, new onset foul-smelling urine) UTI. Note: if the UTI is treated successfully (clinical recovery: confirmed by dipstick test and repeated dipstick test after 14 days [both should be negative]), the subject can be rescreened
    17. a history or presence of any malignancy
    18 uses any drugs that are sensitive cytochrome P450 2D6 (CYP2D6) substrates with a narrow therapeutic index, sensitive P-glycoprotein (Pgp)
    substrates, or moderate or strong cytochrome CYP3A4/5 or P-gp inhibitors or inducers after the start of washout
    19 is using or has used prohibited prior and/or concomitant medication(s) that cannot be discontinued20. known or suspected hypersensitivity to mirabegron or any components of the formulations used
    21. participated in another clinical study (and/or subject has received any investigational therapy within 30 days (or 5 half-lives of the drug, or the limit set by national law, whichever is longer) prior to visit 1/week -4 (screening)
    22. Subject received urinary catheterization within 2 weeks prior to screening
    23. Constipation as defined by the Rome IV criteria that cannot be successfully treated prior to study entry
    24. Female subject who has been pregnant within 6 months prior to screening or breastfeeding within 3 months prior to screening
    25. Subject has any condition which makes the subject unsuitable for study participation
    Additional Exclusion at Visit 3/Week 0 (Baseline)
    Subject has
    26. extraordinary daytime only urinary frequency according to the ICCS definition based on the bladder e-diary
    27. monosymptomatic enuresis confirmed by the bladder e-diary
    28. a maximum voided volume (morning volume excluded) > EBC for age ([age +1] × 30) in mL, based on the bladder e-diary
    29. polyuria defined as voided urine volumes of > 40 mL/kg baseline body weight during 24 hours or > 2.8 L urine for a child weighing ≥ 70 kg (ICCS definition) [Austin et al, 2014], based on bladder e-diary
    30. PVR volume > 20 mL (lowest PVR volume result) as measured by ultrasonography
    31. Subject suffers from a symptomatic (symptoms can include pain, fever, hematuria, new onset foul-smelling urine) UTI. Note: if a symptomatic UTI is present, all visit 3/week 0 (baseline) assessments must be postponed until the UTI is successfully treated (clinical recovery: confirmed by dipstick test and repeated dipstick test after 14 days [both should be negative]), and the urotherapy should continue. The postponed visit 3/week 0 (baseline) should be within 14 days of the intended visit 3/week 0 (baseline)
    32. Subject with hematuria on dipstick test. In the case of hematuria on dipstick test in a female during menstruation, the test can be repeated before randomization (after the end of menstruation)
    33. Subject has a pulse > 99th percentile for age
    Please see protocol for further exclusion criteria
    Exclusión en la visita 1/semana -4 (selección)
    1. El sujeto presenta una frecuencia de la micción extraordinaria únicamente diurna según la definición de la ICCS: -Esto se aplica a niños que sepan ir al baño que tengan la necesidad frecuente de evacuar asociada con pequeños volúmenes de micción solo de forma diurna.
    -La frecuencia de micción diurna es de al menos una vez a la hora con un volumen promedio de evacuación de <50 % de la capacidad esperada de la vejiga (CEV) (normalmente del 10 % al 15 %). -La incontinencia es poco frecuente con ausencia de nicturia. 2. El sujeto tiene una uroflujometría indicativa de otra patología distinta a VH. 3. El sujeto padece enuresis monosintomática. 4. El sujeto padece micción disfuncional. 5. El sujeto tiene obstrucción infravesical, excepto si se ha tratado satisfactoriamente. 6. El sujeto presenta anomalías anatómicas (tratadas quirúrgicamente o no) que afectan a la función de las vías urinarias bajas.
    7. Sujeto con hematuria en prueba con tira reactiva. En el caso de hematuria en la prueba con tira reactiva en un sujeto femenino durante la menstruación, se puede repetir la prueba antes de la aleatorización (tras el final de la menstruación). 8. Sujeto con diabetes insípida.
    9. Sujeto con cálculos renales o vesicales. 10. El sujeto padece IU crónica o ha sufrido más de 3 IU en los 2 meses anteriores a la visita 1/semana -4 (selección). 11. eliminado. 12. El sujeto padece hipertensión en estadio 2 o en estadio 1 no controlada correctamente, según la definición de la Guía práctica clínica de 2017 de la American Academy of Pediatrics. 13. El sujeto presenta un intervalo QTcF >440 ms en el ECG de la fase de selección, riesgo de prolongación de QT (por ejemplo, hipopotasiemia, síndrome de QT largo [LQTS] o antecedentes familiares de LQTS o síncope de esfuerzo) o está tomando medicamentos que prolongan el intervalo QT. 14. El nivel de aspartato transaminasa (AST) o alanina transaminasa (ALT) es >/=2× el límite superior de la normalidad (LSN), o la bilirrubina total (BLT) es >/=1,5× el LSN según la edad y el sexo (los sujetos con el síndrome de Gilbert quedan exceptuados del umbral de bilirrubina). 15. El sujeto presenta insuficiencia renal moderada o leve (filtración glomerular estimada según la fórmula de Schwartz modificada de <60 ml/min por 1,73 m2). 16. El sujeto presenta IU sintomática (los síntomas pueden incluir dolor, fiebre, hematuria y nueva aparición de orina fétida). Nota: Si la IU se trata satisfactoriamente (recuperación clínica: confirmada con prueba con tira reactiva, y repetida transcurridos 14 días de la primera [ambas deben ser negativas]), el sujeto se puede volver a seleccionar. 17. El sujeto tiene antecedentes o presencia de cualquier neoplasia maligna. 18. El sujeto utiliza cualquier fármaco sensible a los sustratos del citocromo P450 2D6 (CYP2D6) con un índice terapéutico estrecho, sensible a los sustratos de la glucoproteína P (P-gp), o inhibidores o inductores fuertes o moderados del citocromo CYP3A4/5 o de la P-gp tras el inicio del periodo de lavado.
    19. El sujeto utiliza o ha utilizado medicamentos concomitantes y/o prohibidos cuyo uso no puede discontinuarse.
    20. El sujeto tiene hipersensibilidad conocida o sospecha de hipersensibilidad al mirabegrón o a cualquier componente de las formulaciones utilizadas. 21. El sujeto ha participado en otro estudio clínico (o ha recibido cualquier tratamiento en fase de investigación en los 30 días (o 5 semividas del fármaco, o según el límite establecido por la legislación nacional, el periodo que sea más largo) anteriores a la visita 1/semana -4 (selección). 22. El sujeto ha sido sometido a un sondaje vesical en las 2 semanas anteriores a la selección. 23. El sujeto padece estreñimiento según los criterios de Roma IV que no se ha podido tratar satisfactoriamente antes de la incorporación al estudio. 24. Sujetos de sexo femenino que hayan estado embarazadas en los 6 meses anteriores a la selección o que hayan estado amamantando en los 3 meses previos a la selección. 25. El sujeto tiene cualquier afección que, en opinión del investigador, incapacita al sujeto para su participación en el estudio. Exclusión adicional en la visita 3/semana 0 (inicio del estudio). 26. El sujeto presenta frecuencia de la micción extraordinaria únicamente diurna según la definición de la ICCS basada en el diario electrónico sobre los hábitos de micción. 27. El sujeto padece enuresis monosintomática confirmada por el diario electrónico sobre los hábitos de micción. 28. El sujeto presenta un volumen de evacuación máximo (excluido el volumen matinal) >CEV para su edad ([edad + 1] × 30) en ml, según el diario electrónico sobre los hábitos de micción.
    Para mas criterios por favor, ver protoclo
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline at the end of the 12-week treatment period: Mean number of micturitions per 24 hours
    Cambio al final del periodo de tratamiento de 12 semanas con respecto al inicio del estudio:
    Número medio de micciones en 24 horas
    E.5.1.1Timepoint(s) of evaluation of this end point
    at the end of the 12-week treatment period
    Al final de la semana 12 del periodo de tratameinto
    E.5.2Secondary end point(s)
    Change from baseline at the end of the 12-week treatment period:
    ○ Mean volume voided per 24 hours
    ○ Maximum volume voided
    ○ Mean number of daytime incontinence episodes per 24 hours
    ○ Mean number of nighttime incontinence episodes per 24 hours
    ○ Mean number of daytime micturitions per 24 hours
    ● Number of dry (incontinence-free) days per 7 days at the end of the
    12-week treatment
    ● Nature, frequency and severity of AEs
    ● Clinical laboratory tests (hematology, biochemistry and urinalysis)
    ● Vital signs (blood pressure and pulse)
    ● Routine 12-lead ECG
    ● PVR volume
    ● Acceptability and palatability questionnaire
    ● Steady-state Cmax, AUCtau, Ctrough, Tmax, CL/F, and Vz/F. Additional parameters may be calculated based on the population pharmacokinetic model used
    - Cambio al final del periodo de tratamiento de 12 semanas con respecto al inicio del estudio:
    --Volumen medio evacuado en 24 horas
    --Volumen máximo evacuado
    --Número medio de episodios de incontinencia diurna en 24 horas
    --Número medio de episodios de incontinencia nocturna en 24 horas
    --Número medio de micciones diurnas en 24 horas
    - Número de días sin incontinencia en 7 días al final del periodo de tratamiento de 12 semanas
    - Naturaleza, frecuencia y gravedad de los AA
    - Pruebas clínicas de laboratorio (hematología, bioquímica y análisis de orina)
    - Constantes vitales (presión arterial y pulso)
    - ECG de 12 derivaciones ordinario
    - Volumen de OR (orina residual)
    - Cuestionario de aceptabilidad y palatabilidad
    - Cmáx en equilibrio, AUCtau, Cmín, Tmáx, CL/F y Vz/F. Los parámetros adicionales pueden calcularse según el modelo farmacocinético de población utilizado.
    E.5.2.1Timepoint(s) of evaluation of this end point
    throughout and at the end of the 12-week treatment period
    A lo largo de y al final de la semana 12 del periodo de tratamiento
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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) 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
    sequential dose titration
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    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
    Denmark
    France
    Germany
    Italy
    Korea, Democratic People's Republic of
    Malaysia
    Mexico
    Netherlands
    Norway
    Philippines
    Poland
    Russian Federation
    Serbia
    South Africa
    Spain
    Turkey
    Ukraine
    United Kingdom
    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
    Última Visita del Último Paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    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 Yes
    F.1.1Number of subjects for this age range: 432
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 368
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 64
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects may be hospitalized for medical care under direction of their parents or PI's decision
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 226
    F.4.2.2In the whole clinical trial 432
    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)
    The Sponsor does not provide trial medication or replacement for mirabegron oral suspension or tablets after study.
    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 Decision2021-10-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-08-27
    P. End of Trial
    P.End of Trial StatusOngoing
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