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    Summary
    EudraCT Number:2015-000507-44
    Sponsor's Protocol Code Number:D-FR-52120-223
    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:2016-03-18
    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 number2015-000507-44
    A.3Full title of the trial
    A PHASE III, MULTICENTRE, RANDOMISED, DOUBLE BLIND, PARALLEL GROUP, PLACEBO CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF ONE OR MORE INTRADETRUSOR TREATMENTS OF 600 OR 800 UNITS OF DYSPORT® FOR THE TREATMENT OF URINARY INCONTINENCE IN SUBJECTS WITH NEUROGENIC DETRUSOR OVERACTIVITY DUE TO SPINAL CORD INJURY OR MULTIPLE SCLEROSIS
    Estudio en fase III, multicéntrico, aleatorizado, doble ciego, de grupos paralelos y controlado con placebo para evaluar la eficacia y la seguridad de uno o más tratamientos intradetrusor con 600 u 800 unidades de Dysport® para el tratamiento de la incontinencia urinaria en pacientes con hiperactividad neurógena del detrusor por lesión de la médula espinal o esclerosis múltiple.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate DYSPORT® for the treatment of subjects with loss of bladder control and involuntary urination as a result of spinal cord injury or multiple sclerosis
    Estudio para investigar Dysport® para el tratamiento de pacientes con pérdida de control de la vejiga e incontinencia urinaria por lesión de la médula espinal o esclerosis múltiple.
    A.4.1Sponsor's protocol code numberD-FR-52120-223
    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 SponsorIpsen Innovation
    B.1.3.4CountryFrance
    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 supportIpsen Innovation
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIpsen Innovation
    B.5.2Functional name of contact pointGlobal Drug Development
    B.5.3 Address:
    B.5.3.1Street AddressZ.I. de Courtaboeuf, 5 Avenue du Canada
    B.5.3.2Town/ cityLes Ulis Cedex
    B.5.3.3Post code91940
    B.5.3.4CountryFrance
    B.5.6E-mailct-application@ipsen.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 Dysport®
    D.2.1.1.2Name of the Marketing Authorisation holderIPSEN BIOPHARM LTD (WREXHAM, UK)
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameDysport®
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravesical use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCLOSTRIDIUM BOTULINUM TOXIN TYPE A
    D.3.9.1CAS number 93384-43-1
    D.3.9.2Current sponsor code52120
    D.3.9.3Other descriptive nameBOTULINUM TOXIN A - HAEMAGGLUTININ COMPLEX
    D.3.9.4EV Substance CodeSUB77183
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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 Yes
    D.3.11.13.1Other medicinal product typeToxin
    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 Dysport®
    D.2.1.1.2Name of the Marketing Authorisation holderIPSEN BIOPHARM LTD (WREXHAM, UK)
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameDysport®
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravesical use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCLOSTRIDIUM BOTULINUM TOXIN TYPE A
    D.3.9.1CAS number 93384-43-1
    D.3.9.2Current sponsor code52120
    D.3.9.3Other descriptive nameBOTULINUM TOXIN A - HAEMAGGLUTININ COMPLEX
    D.3.9.4EV Substance CodeSUB77183
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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 Yes
    D.3.11.13.1Other medicinal product typeToxin
    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 placeboPowder for solution for injection
    D.8.4Route of administration of the placeboIntravesical use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboPowder for solution for injection
    D.8.4Route of administration of the placeboIntravesical use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Urinary incontinence caused by neurogenic detrusor overactivity due to either spinal cord injury or multiple sclerosis
    Incontinencia urinaria provocada por hiperactividad neurógena del detrusor por lesión de la médula espinal o esclerosis múltiple
    E.1.1.1Medical condition in easily understood language
    Loss of bladder control and involuntary urination due to either spinal cord injury or multiple sclerosis
    Pérdida de control de la vejiga e incontinencia urinaria por lesión de la médula espinal o esclerosis múltiple
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10046543
    E.1.2Term Urinary incontinence
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To assess the efficacy of two Dysport® doses (600 units (U) and 800 U), compared to placebo in reducing UI from Baseline to Week 6 following the first investigational medicinal product (IMP) administration.
    Evaluar la eficacia de dos dosis de Dysport® (600 unidades (U) y 800 U), comparado con placebo a la hora de reducir la IU desde la visita inicial a la semana 6 después de la primera administración del producto en fase de investigación (PEI).
    E.2.2Secondary objectives of the trial
    - To assess the efficacy of two Dysport® doses (600 U and 800 U), compared to placebo in improving bladder diary measures, urodynamic and patient-reported efficacy endpoints following the first IMP administration, including assessing duration of effect.

    - To assess the efficacy of two Dysport® doses (600 U and 800 U) in improving bladder diary measures, urodynamic and patient-reported efficacy endpoints following retreatment IMP administrations, including assessing duration of effect.

    - To assess the safety of two Dysport® doses (600 U and 800 U) for the treatment of UI due to NDO.
    - Evaluar la eficacia de dos dosis de Dysport® (600 U y 800 U), comparado con placebo a la hora de mejorar las mediciones diarias de la vejiga, el estudio urodinámico y los criterios de valoración de la eficacia comunicados por el paciente después de la primera administración del PEI, incluida la evaluación de la duración del efecto.

    - Evaluar la eficacia de dos dosis de Dysport® (600 U y 800 U), a la hora de mejorar las mediciones diarias de la vejiga, el estudio urodinámico y los criterios de valoración de la eficacia comunicados por el paciente después de las administraciones del PEI al repetir el tratamiento, incluida la evaluación de la duración del efecto.

    - Evaluar la seguridad de dos dosis de Dysport® (600 U y 800 U), para el tratamiento de la IU por HND.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The following inclusion criteria will be assessed at the beginning of the Screening process:

    1) Written informed consent prior to any study-related procedure.

    2) Male or female, aged 18 to 80 years inclusive.

    3) UI for at least 3 months prior to Screening as a result of NDO due to SCI or MS.

    4) Subjects with SCI must have a stable neurological injury at T1 level or below which occurred at least 6 months prior to Screening.
    OR
    Subjects with MS must be clinically stable in the investigator?s opinion, with no exacerbation (relapse) of MS for at least 3 months prior to Screening.

    5) Subjects in the non-urodynamic subset only, must have NDO (defined as the presence of involuntary detrusor contractions during the storage phase of urodynamic filling cystometry) on a historic urodynamic assessment performed in the 12 months prior to Screening
    - If urodynamics are not performed in the 12 months prior to Screening or if results are not available, then a urodynamic filling cystometry assessment must be performed during Screening, per local practice (see inclusion criterion # 16).

    6) Subjects must have had an inadequate response after at least 4 weeks of oral medications used in the treatment of NDO (e.g. anticholinergics, beta-3 agonists)and/or have intolerable side-effects.

    7) Subjects who are to continue on concomitant oral medications for NDO during the study must be on a stable dose for at least 4 weeks prior to Screening.

    8) Subjects who are to continue on concomitant oral medications for NDO during the study must be willing to continue on the same medications and doses during Screening and for at least 12 weeks following the first IMP administration.

    9) Routinely performing CIC to ensure adequate bladder emptying (regularly performing CIC at a regimen of every 4?6 hours during waking hours, or more frequently). CIC regimen must be stable for at least 4 weeks prior to Screening (CIC may be performed by the subject or caregiver).

    10) Subjects must be willing to continue on the same CIC regimen during Screening and for at least 12 weeks following the first IMP administration.

    11) Female subjects of childbearing potential must have a negative pregnancy test result and be willing to use reliable contraceptive measures throughout study participation. Reliable forms of contraception include but are not limited to:
    - hormonal contraceptives (e.g. oral, patch, injection)
    - double barrier (e.g. male condom plus spermicide, or female diaphragm plus spermicide)
    - intrauterine device
    - male partner has had a vasectomy
    - total abstinence from intercourse with male partners (periodic abstinence is not acceptable).
    Female subjects meeting any of the following criteria are not considered to be of childbearing potential:
    - postmenopausal (>=47 years of age and amenorrhoeic for at least 12 consecutive months)
    - have been sterilised surgically (e.g. bilateral tubal ligation)
    - have had a hysterectomy
    - have had a bilateral oophorectomy.

    12) Documented urinary tract ultrasound is available in the 6 months prior to Screening, confirming that no medical issues exist that would preclude entry to the study (e.g. bladder stones or unexplained renal mass).
    - If not performed in the 6 months prior to Screening or results are not available, then a urinary tract ultrasound must be conducted during Screening.

    13) Ability to complete all study requirements in the opinion of the investigator, including regularly completing the 7-day bladder diary and attending all scheduled study visits. The caregiver may assist with the completion of study documentation and procedures (including the bladder diary and questionnaires), if required.

    The following inclusion criteria will be assessed following completion of screening bladder diary:

    14) An average of at least two episodes per day of UI recorded on the screening bladder diary.

    15) No more than two incontinent-free days documented on the screening bladder diary.

    The following inclusion criterion will be assessed following completion of screening urodynamic assessment (if required):

    16) NDO (defined as the presence of involuntary detrusor contractions (IDCs) during the storage phase of urodynamic filling cystometry) on:
    - standardised study specific urodynamics (all subjects in urodynamic subset)
    - local site practice urodynamics (subjects in the non-urodynamic subset without a documented urodynamic assessment in the 12 months prior to Screening)
    Los siguientes criterios de inclusión se evaluarán al principio del proceso de selección:
    1) Consentimiento informado por escrito antes de cualquier procedimiento del estudio.
    2) Hombre o mujer de 18 a 80 años de edad, ambos inclusive.
    3) IU durante 3 meses mínimo antes de selección, como resultado de HND por LME o EM.
    4) Los pacientes con LME deben tener una lesión neurológica estable a nivel de T1 o inferior que haya tenido lugar 6 meses mínimo antes de selección.
    O
    pacientes con EM deben estar cínicamente estables en opinión del investigador, sin reagudización de EM durante 3 meses mínimo antes de selección.
    5) Solo pacientes del subgrupo sin estudio urodinámico deben tener HND (definida como la presencia de contracciones involuntarias del detrusor durante la fase de almacenamiento de la cistometría de llenado en el estudio urodinámico) en un estudio urodinámico histórico realizado en 12 meses anteriores a selección.
    Si el estudio urodinámico no se ha realizado en 12 meses anteriores a selección o los resultados no están disponibles, deberá hacerse un estudio urodinámico con evaluación de cistometría de llenado durante selección, según práctica local (ver criterio inclusión n.° 16).
    6) Los pacientes deben haber tenido una respuesta inadecuada tras 4 semanas como mínimo de medicación por vía oral empleada en el tto de HND (p. ej., anticolinérgicos, agonistas beta-3) y/o tener efectos secundarios intolerables.
    7) Los pacientes que van a continuar recibiendo medicación concomitante por vía oral para la HND durante el estudio deben estar recibiendo dosis estable durante 4 semanas mínimo antes de selección.
    8) Los pacientes que van a continuar recibiendo medicación concomitante por vía oral para HND durante el estudio deben estar dispuestos a seguir con la misma medicación y dosis durante selección y 12 semanas mínimo tras primera administración del PEI.
    9) Realización de SIL periódicos para garantizar vaciado adecuado de la vejiga (realización de SIL frecuentes cada 4-6 horas durante horas de vigilia, o mayor frecuencia). La pauta de SIL debe ser estable durante 4 semanas mínimo antes de selección (el SIL lo puede realizar el paciente o el cuidador).
    10) Los pacientes deben estar dispuestos a continuar con la misma pauta de SIL durante selección y 12 semanas mínimo tras primera administración del PEI.
    11) Las mujeres con capacidad de procrear deben haber dado negativo en prueba de embarazo y estar dispuestas a usar métodos anticonceptivos fiables durante su participación en el estudio. Algunos métodos anticonceptivos fiables son, entre otros:
    - anticonceptivos hormonales (p. ej. píldora, parche o inyecciones)
    - de doble barrera (p. ej. preservativo masculino y espermicida o diafragma femenino y espermicida)
    - dispositivo intrauterino
    - que la pareja masculina se haya sometido a una vasectomía
    - abstinencia total de relaciones sexuales con hombres (la abstinencia periódica no se acepta)
    Las mujeres que cumplan cualquiera de los siguientes criterios no se consideran con capacidad de procrear:
    - postmenopáusicas (>= 47 años de edad y con amenorrea durante 12 meses consecutivos como mínimo)
    - haber sido esterilizadas quirúrgicamente (por ligadura de trompas, p. ej)
    - haberse sometido a una histerectomía
    - haberse sometido a una ovariectomía bilateral
    12) Se debe disponer de una ecografía de vías urinarias en 6 meses previos a selección que confirme que no existen problemas médicos que impedirían la entrada al estudio (p. ej., litiasis vesical o masa renal sin causa aparente).
    - Si no se ha realizado en 6 meses anteriores a selección o los resultados no estuvieran disponibles, deberá realizarse una ecografía de vías urinarias durante selección.
    13) Capacidad de completar todos los requisitos del estudio a criterio del investigador, que incluyen rellenar diario vesical de 7 días con regularidad y asistir a todas las visitas del estudio. El cuidador podrá asistir a la hora de rellenar documentación y completar procedimientos del estudio (incluidos diario vesical y cuestionarios), si fuera necesario.
    Se evaluarán los siguientes criterios de inclusión una vez que se haya rellenado diario vesical de selección:
    14) Al menos dos episodios /día de media de IU registrados en diario vesical de selección.
    15) Dos días máximo sin incontinencia documentados en diario vesical de selección.
    Se evaluará el siguiente criterio de inclusión una vez que se haya completado estudio urodinámico de selección (si necesario):
    16) HND (definida como presencia de [CID] durante fase de almacenamiento de cistometría de llenado en estudio urodinámico) en:
    - Estudio urodinámico específico normalizado (todos los pacientes del subgrupo urodinámico).
    - Estudio urodinámico según práctica local del centro (pacientes del subgrupo sin estudio urodinámico, que no tienen un estudio urodinámico documentado en 12 meses anteriores a selección).
    E.4Principal exclusion criteria
    The following exclusion criteria will be assessed throughout the Screening process:

    1) Any current condition (other than NDO) that may impact on bladder function, including but not limited to:
    - predominant stress UI (rather than NDO-related incontinence)
    - bladder stones
    - current symptomatic urinary tract infection
    - current active genitourinary infection, e.g. genital warts
    - uterine prolapse
    - cystocele
    - rectocele.
    Mild uterine prolapse, cystocele or rectocele that does not impact on bladder function
    is not exclusionary.

    2) Previous or current, tumour or malignancy affecting the spinal column or spinal cord, or any other nonstable cause of SCI.

    3) Surgery less than 6 months prior to Screening for bladder stones.

    4) Surgery less than 6 months prior to Screening for uterine prolapse, cystocele or rectocele.

    5) Previous open surgery for NDO, e.g. augmentation cystoplasty.

    6) Previous urethral stent placement or sphincterotomy.

    7) Previous or current diagnosis of, or symptoms/signs/investigations suggestive of, significant urological or pelvic disease, including but not limited to:
    - urinary tract malignancy (e.g. bladder, prostate, urethral or kidney cancer)
    - hydronephrosis
    - interstitial cystitis/bladder pain syndrome
    - müllerian duct cysts
    - radiation cystitis
    - genitourinary tuberculosis.

    8) Previous or current uninvestigated haematuria. Subjects with investigated haematuria may enter the study if significant urological/renal pathology has been ruled out to the satisfaction of the investigator.

    9) Any condition that will prevent cystoscopic treatment administration or CIC usage e.g. urethral strictures.

    10) Current indwelling bladder catheter, or removal of indwelling bladder catheter less than 4 weeks prior to Screening.

    11) BTX-A treatment within 9 months prior to Screening for any urological condition
    (e.g. detrusor or urethral sphincter treatments).

    12) BTX-A treatment within 3 months prior to Screening for any non-urological condition.

    13) Bladder instillation with any pharmacologic agent less than 3 months prior to
    Screening.

    14) Use of capsaicin or resiniferatoxin less than 6 months prior to Screening.

    15) Any neuromodulation/electrostimulation usage for urinary symptoms/incontinence
    within 4 weeks prior to Screening. Any implanted neuromodulation device must be switched off at least 4 weeks prior to Screening and must remain off throughout study participation.

    16) Any concomitant therapy usage that, in the investigator?s opinion, would interfere with the evaluation of safety or efficacy of the IMP, and/or confound the study results.

    17) History of chronic drug or alcohol abuse.

    18) Female subject who is pregnant or planning to become pregnant during the study, or is currently lactating (breastfeeding).

    19) Any medical condition or disease that might interfere with neuromuscular function, e.g. diagnosed myasthenia gravis, Lambert-Eaton syndrome or amyotrophic lateral
    sclerosis.

    20) Use of medications that affect neuromuscular transmission, such as curare-like depolarising agents, lincosamides, polymyxins, anticholinesterases and aminoglycoside antibiotics.

    21) Previous primary or secondary non response to any botulinum toxins for the targeted condition.

    22) Known hypersensitivity to BTX-A or to any components in the IMP formulation (including cow?s milk protein).

    23) History of allergy to, or intolerance to, the anaesthetic or antibiotic agents that the investigator intends to use during the study.

    24) Unable to stop medications with anticoagulant/antiplatelet effects for at least 3 days prior to each IMP administration and to recommence the day following each IMP administration (low molecular weight heparins may be used within 3 days of IMP administration).

    25) Any condition that may cause excessive bleeding (e.g. haemophilia or clotting factor deficiencies).

    26) Any condition or situation which, in the investigator?s opinion, puts the subject at significant risk, may confound the study results, or may interfere with the subject?s participation in the study.

    27) Treatment with any new investigational drug or device in the 4 weeks prior to Screening or scheduled to be used during the study period. In addition, at least 5 elimination half-lives must have occurred since discontinuing any new investigational drug prior to Screening.

    The following exclusion criteria will be assessed following completion of screening bladder diary and when screening laboratory blood results become available:

    28) Voided urine volume >=3 L during a single 24-hour period on the screening bladder diary.

    29) Serum creatinine >=2 times the upper limit of normal on screening serum chemistry testing.
    Los siguientes criterios de exclusión se evaluarán durante todo el proceso de selección:
    1) Cualquier enfermedad actual (ajena a la HND) que pueda afectar a función de vejiga, como, p.ej:
    - IU de esfuerzo predominante (en lugar de incontinencia relacionada con la HND)
    - litiasis vesical
    - infección de vías urinarias sintomática en curso
    - infección genitourinaria activa en curso, como condiloma acuminado
    - prolapso uterino
    - cistocele
    - rectocele
    El prolapso uterino, cistocele o rectocele leves que no afecten a la función de la vejiga no serán excluyentes.
    2) Tumor o neoplasia maligna anterior o actual que afecten a columna vertebral o a médula espinal, o cualquier otra causa no estable de LME.
    3) Cirugía por litiasis vesical en últimos 6 meses previos a selección.
    4) Cirugía por prolapso uterino, cistocele o rectocele en últimos 6 meses previos a selección.
    5) Cirugía abierta anterior por HND, p.ej por cistoplastia de aumento.
    6) Colocación anterior de prótesis intrauretral o esfinterotomía.
    7) Diagnóstico anterior o actual (o síntomas/signos/investigaciones que sugieran) de afecciones urológicas o pélvicas significativas, incluidas, entre otras:
    - neoplasia maligna urinaria (cáncer de vejiga, próstata, uretra o riñón, p.ej)
    - hidronefrosis
    - cistitis intersticial/síndrome de dolor vesical
    - quistes en conducto de Müller
    - cistitis por radiación
    - tuberculosis genitourinaria
    8) Hematuria anterior o actual no investigada. Los pacientes con hematuria investigada podrán entrar al estudio si han descartado patologías urológicas/renales significativas a satisfacción del investigador.
    9) Cualquier afección que impida administración del tto cistoscópico o uso de SIL, como estenosis uretral.
    10) Tener catéter permanente en vejiga en la actualidad o que se haya retirado en 4 semanas previas a selección.
    11) Tto con BTX-A en 9 meses anteriores a selección por cualquier afección urológica (p. ej., tratamientos del detrusor o del esfínter uretral).
    12) Tto con BTX-A en 3 meses anteriores a selección por cualquier afección no urológica.
    13) Instilación en vejiga de fármaco en 3 meses anteriores a selección.
    14) Uso de capsiacina o resiniferatoxina en 6 meses anteriores a selección.
    15) Cualquier uso de neuromodulación/electroestimulación para síntomas urinarios/incontinencia en 4 semanas anteriores a selección. Todo dispositivo de neuromodulación implantado debe desactivarse 4 semanas mínimo antes de selección y debe permanecer desactivado durante la participación en estudio.
    16) Cualquier tto concomitante que, a criterio del investigador, pueda interferir con evaluación de la seguridad y eficacia del PEI y/o confunda los resultados del estudio.
    17) Antecedentes de drogadicción o alcoholismo.
    18) Mujer embarazada, o que esté planeando quedarse embarazada durante el estudio o que esté dando el pecho actualmente.
    19) Cualquier afección médica o enfermedad que puede interferir con funcionamiento neuromuscular, p.ej, diagnóstico de miastenia grave, síndrome de Lambert-Eaton o esclerosis lateral amiotrófica.
    20) Uso de medicación que afecte transmisión neuromuscular, como medicamentos curarizantes despolarizantes, lincosamidas, polimixinas, anticolinesterasas y aminoglucósidos.
    21) No haber mostrado respuesta principal o secundaria anteriormente a ninguna toxina botulínica para enfermedad objetivo.
    22) Hipersensibilidad conocida a la BTX-A o a cualquier componente de formulación del PEI (incluida proteína de leche de vaca).
    23) Antecedentes de alergia o intolerancia a anestésicos o antibióticos que el investigador pretende usar durante estudio
    24) No haber podido dejar de tomar medicación con efectos anticoagulantes/antiplaquetarios durante al menos 3 días antes de cada administración del PEI (se podrán usar heparinas de bajo peso molecular en 3 días previos a administración del PEI).
    25) Cualquier afección que pueda provocar hemorragia excesiva (p. ej., hemofilia o deficiencias de factores de coagulación).
    26) Cualquier afección o situación que, en opinión del investigador, suponga riesgo significativo para el paciente, pueda confundir resultados del estudio o pueda interferir con participación del paciente en el estudio.
    27) Un tto con cualquier fármaco o dispositivo nuevo en investigación en 4 semanas previas a selección o que se haya programado para usarse durante el período del estudio. Además, deben haber transcurrido al menos 5 semividas de eliminación desde la interrupción de cualquier fármaco nuevo en investigación antes de selección.
    Los siguientes criterios de exclusión se evaluarán tras completar diario vesical de selección y cuando disponibles resultados de análisis de sangre de selección:
    28) Volumen de orina vaciada >=3 l durante un período de 24 horas en diario vesical de selección.
    29) Creatinina sérica >= 2 veces mayor que límite superior de normalidad en pruebas de bioquímica sérica de selección.
    E.5 End points
    E.5.1Primary end point(s)
    - Mean change from study Baseline (assessed at Screening) to Week 6 after the first IMP administration in the weekly number of UI episodes:
    - measured on a 7-day bladder diary.
    -Media del cambio entre la visita inicial del estudio (evaluado en la selección) y la semana 6 después de la primera administración del PEI en la cantidad semanal de episodios de IU:
    - medidos en un diario vesical de 7 días
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 6
    Semana 6
    E.5.2Secondary end point(s)
    Bladder diary measures:
    - weekly number of UI episodes
    - daily urinary frequency (total, spontaneous void only, CIC only)
    - 24-hour voided volume (total, spontaneous void only, CIC only)
    - volume per void (total, spontaneous void only, CIC only).

    Urodynamic measures (urodynamic subset only):
    - maximum cystometric capacity (MCC)
    - maximum detrusor pressure (MDP) during storage
    - volume at first involuntary detrusor contraction (Vol@1stIDC)
    - maximum detrusor pressure at first involuntary detrusor contraction (PdetMax@1stIDC)
    - end fill pressure (EFP)
    - detrusor compliance (DC).

    Patient-reported outcome questionnaires:
    - incontinence quality of life (I-QoL) total summary score
    - EuroQol 5-dimension 5-level (EQ-5D-5L)
    - modified patient global impression - improvement (mPGI-I) score.

    Proportion of subjects at post-treatment timepoints following the first and subsequent
    treatments with:
    - no episodes of UI (i.e. continence is achieved)
    - UI response at several levels (i.e. >=30% improvement, >=50% improvement,
    >=75% improvement, etc.)
    - no IDCs on urodynamic assessment (i.e. urodynamic cure is achieved) (urodynamic subset only).

    Duration of effect following the first and subsequent treatments measured by:
    ? time to request retreatment
    ? time to eligibility for retreatment
    ? time between treatments.
    Mediciones del diario vesical:
    - cantidad semanal de episodios de IU
    - frecuencia urinaria diaria (total, solo micción espontánea, solo SIL)
    - volumen orinado en 24 horas (total, solo micción espontánea, solo SIL)
    - volumen por micción (total, solo micción espontánea, solo SIL)

    Mediciones urodinámicas (solo el subgrupo urodinámico):
    - capacidad cistométrica máxima (CCM)
    - presión máxima del detrusor (PMD) durante el almacenamiento
    - volumen de la primera contracción involuntaria del detrusor (Vol@1ªCID)
    - presión máxima del detrusor en la primera contracción involuntaria del detrusor (PmáxDet@1ªCID)
    - presión de llenado final (PLlF)
    - distensibilidad del detrusor (DD)

    En cuestionarios sobre resultados comunicados por el paciente:
    - puntuación total de resumen de la calidad de vida con incontinencia (CdV-I)
    - cuestionario EuroQoL de 5 dimensiones y 5 niveles (EQ-5D-5L)
    - puntuación de la impresión global del paciente modificada - mejoría (IGPm-M).

    Proporción de pacientes en los momentos posteriores al tratamiento después de los tratamientos inicial y posteriores, con:
    - ningún episodio de IU (es decir, se logra la continencia)
    - respuesta de la IU en diferentes niveles (es decir, >= 30 % de mejoría, >= 50 % de mejoría, >= 75 % de mejoría, etc.)
    - sin CID en el estudio urodinámico (es decir, se logra la curación urodinámica) (solo en el subgrupo urodinámico)

    La duración del efecto después de los tratamientos inicial y posteriores, medida mediante:
    - el tiempo hasta la solicitud de repetición del tratamiento
    - el tiempo hasta la idoneidad para la repetición del tratamiento
    - el tiempo entre tratamientos
    E.5.2.1Timepoint(s) of evaluation of this end point
    Refer to schedule of events in protocol
    Véase calendario en protocolo.
    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 No
    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 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 trial4
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA42
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Belgium
    Brazil
    Chile
    Colombia
    France
    Germany
    Israel
    Mexico
    New Zealand
    Peru
    Russian Federation
    Spain
    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
    UVUP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months9
    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: 306
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 102
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 124
    F.4.2.2In the whole clinical trial 408
    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)
    Standard of care
    Tratamiento standard.
    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 Decision2016-05-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-04
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