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    Summary
    EudraCT Number:2018-003941-41
    Sponsor's Protocol Code Number:0170
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-06-11
    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 number2018-003941-41
    A.3Full title of the trial
    A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of TD-9855 in Treating Symptomatic Neurogenic
    Orthostatic Hypotension in Subjects with Primary Autonomic Failure
    Estudio en fase III, de 22 semanas de duración, multicéntrico, de retirada aleatorizada, de TD-9855 en el tratamiento de la hipotensión ortostática neurogénica sintomática en sujetos con fallo autonómico primario
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This study will look at whether an investigational drug, called TD-9855, works and how safe it is when taken over a longer period of time to treat symptomatic neurogenic orthostatic hypotension (snOH) in people with Parkinson’s disease (PD), multiple system atrophy (MSA), or pure autonomic failure (PAF). It will also look at the effects of TD-9855 on general well-being and whether it can improve symptoms of neurogenic OH (nOH)
    Este estudio analizará si un medicamento en investigación, llamado TD-9855, funciona y como es de seguro cuando se toma durante un período más prolongado para tratar la hipotensión ortostática neurogénica sintomática (snOH) en personas con la enfermedad de Parkinson, atrofia múltiple del sistema (MSA), o fallo autonómico primario (PAF). También examinará los efectos del TD-9855 sobre el bienestar general y si puede mejorar los síntomas de la hipotensión ortostática neurogénica (nOH)
    A.3.2Name or abbreviated title of the trial where available
    Redwood
    A.4.1Sponsor's protocol code number0170
    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 SponsorTheravance Biopharma Ireland Limited
    B.1.3.4CountryIreland
    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 supportTheravance Biopharma Ireland Limited
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTheravance Biopharma Ireland Limited
    B.5.2Functional name of contact pointDr. Brett Haumann
    B.5.3 Address:
    B.5.3.1Street AddressConnaught House, 1 Burlington Road
    B.5.3.2Town/ cityDublin 4
    B.5.3.3Post codeD04 C5Y6
    B.5.3.4CountryIreland
    B.5.4Telephone number+353(0)1 539 4800
    B.5.6E-mailbhaumann@theravance.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.3.2Product code TD-9855
    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 INNampreloxetine hydrochloride
    D.3.9.1CAS number 1227056-84-9
    D.3.9.2Current sponsor codeTD-9855
    D.3.9.3Other descriptive nameTD-9855
    D.3.9.4EV Substance CodeSUB194904
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure
    Hipotensión ortostática neurogénica sintomática (snOH) en sujetos con fallo autonómico primario
    E.1.1.1Medical condition in easily understood language
    symptomatic neurogenic Orthostatic Hypotension (snOH) in people with Parkinson's disease (PD), multiple system atrophy (MSA) or pure autonomic failure (PAF)
    Hipotensión ortostática neurogénica sintomática (snOH) en personas con la enfermedad de Parkinson, atrofia múltiple del sistema (MSA) o fallo autonómico primario (PAF)
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    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 durability of effect of TD-9855 in subjects with symptomatic neurogenic orthostatic hypotension (snOH) due to multiple system atrophy (MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) compared with placebo (PBO) over a double-blind, randomized withdrawal period of 6 weeks following an open label (OL) treatment of 16 weeks.

    To evaluate the safety and tolerability of TD-9855 when taken for up to 22 weeks.
    Evaluar la durabilidad del efecto de TD-9855 en sujetos con hipotensión ortostática neurogénica sintomática (snOH) debido a atrofia multisistémica (AMS), enfermedad Parkinson (EP) o fallo autonómico puro (FAP) comparado con placebo (PBO) a lo largo de periodo de retirada aleatorizado doble ciego de 6 semanas después del tratamiento en la fase de estudio abierto (FeA) durante 16 semanas.

    Evaluar la seguridad y la tolerabilidad de TD-9855 cuando se toma durante un máximo de 22 semanas.
    E.2.2Secondary objectives of the trial
    To evaluate the durability of effect of TD-9855 by symptom and activity assessments using Orthostatic Hypotension Symptom Assessment (OHSA) and Orthostatic Hypotension Daily Activity Scale (OHDAS).

    To evaluate the effect of TD-9855 using disease-specific instruments and generic quality of life assessment.

    To evaluate subject’s symptomatic improvement as measured by a wearable device.

    To evaluate the effect of TD-9855 using standing blood pressure during orthostatic standing test.
    Evaluar la durabilidad del efecto de TD-9855 mediante las evaluaciones de los síntomas y de la actividad utilizando la evaluación de los síntomas de la hipotensión ortostática (Orthostatic Hypotension Symptom Assessment, OHSA) y la escala de actividad diaria de la hipotensión ortostática (Orthostatic Hypotension Daily Activity Scale, OHDAS).

    Evaluar el efecto de TD-9855 utilizando instrumentos específicos de la enfermedad y una evaluación de la calidad de vida genérica.

    Evaluar la mejora sintomática del sujeto medida mediante un dispositivo portátil.

    Evaluar la eficacia de TD-9855 mediante la tensión arterial en bipedestación durante una prueba de posición ortostática.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria (For 0169 Completers Group):
    1. Completion of 4 weeks of double blind treatment in Study 0169 (V6) and, in the opinion of the Investigator, could benefit from continued treatment with TD-9855. No minimum score of OHSA#1 is required to enter V1 of Study 0170.
    2. The subject has a minimum of 80% study medication compliance in Study 0169.
    3. The subject must be able to understand the nature of the study and must provide written informed consent prior to the conduct of any study procedures (including an understanding that entry to Study 0170 may result in changes occurring in the subject’s current therapeutic regimen).
    4. The subject must be willing to continue on treatment regardless of the possibility of randomization to either TD-9855 or PBO during the randomized withdrawal phase and must continue to meet the inclusion criteria for the preceding study (Study 0169) with the exception that tilt-table test, ESC review and approval of eligibility are not required for entry into Study 0170.

    Inclusion Criteria (For De Novo Group):
    1. Subject is male or female and at least 30 years old.
    2. If subject is female, the subject must be non-pregnant and non-lactating. A woman of childbearing potential, must have a documented negative pregnancy test at screening.
    NOTE: A woman is considered to be of childbearing potential unless she is postmenopausal (amenorrheic for at least 2 years) or documented to be surgically sterile (bilateral tubal ligation or total hysterectomy). A female subject may be admitted to the study on the basis of a negative urine pregnancy test. If the urine beta human chorionic gonadotropin (bHCG) test is positive, a serum bHCG test must be performed. The pregnancy test must be confirmed negative for a subject to be eligible for this study.
    3. During the study and for 30 days after receiving the last dose of the study drug, females of childbearing potential or males capable of fathering children must agree to use highly effective birth control measures (failure rate <1% when used consistently and correctly) or agree to abstain from sexual intercourse.
    4. Subject must meet the diagnostic criteria of nOH, as demonstrated by a sustained reduction in BP of ≥20 mmHg (systolic) or ≥10 mmHg (diastolic) within 3 min of being tilted-up ≥60 degrees from a supine position as determined by a tilt-table test.
    5. Subject must score at least a 4 on the OHSA#1 at V1.
    6. For subjects with PD only: Subject has a diagnosis of PD according to the United Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank Criteria (1992).
    7. For subjects with MSA only: Subject has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman Criteria (2008).
    8. For subjects with PAF only: Subject has impaired autonomic reflexes, as determined by absence of Phase IV BP overshoot after release of the Valsalva strain.
    9. Subject has plasma NE levels ≥ 100 pg/mL after being in seated position for 30 minutes.
    10. Subject is willing and able to provide signed and dated written informed consent to participate prior to initiation of any study related procedures.
    11. Subject is able to communicate well with the investigator and understand clinic staff, understands the expectations of the study and is able to comply with the study procedures, requirements, and restrictions.
    Criterios de inclusión (para el Grupo que completó el 0169):
    1. Haber completado 4 semanas de tratamiento doble ciego en el Estudio 0169 (V6) y, en opinión del investigador, poder beneficiarse del tratamiento continuado con TD-9855. No se requiere ninguna puntuación mínima de OHSA#1 para pasar a la V1 del Estudio 0170.
    2. Contar con un 80 % de cumplimiento de la medicación del estudio como mínimo en el Estudio 0169.
    3. El sujeto debe ser capaz de entender la naturaleza del estudio y proporcionar su consentimiento informado por escrito antes de la realización de cualquier procedimiento del estudio (incluida la comprensión de que la entrada en el Estudio 0170 puede dar lugar a que se produzcan cambios en la pauta terapéutica actual del sujeto).
    4. El sujeto debe estar dispuesto a continuar con el tratamiento, independientemente de la posibilidad de que la aleatorización sea a TD-9855 o a placebo durante la fase de retirada aleatorizada y debe seguir cumpliendo los criterios de inclusión del estudio anterior (Estudio 0169) con la excepción de que la prueba de la mesa inclinada, la revisión del ESC y la aprobación de la idoneidad no sean necesarias para la entrada en el Estudio 0170.

    Criterios de inclusión (para el Grupo de Novo):
    1. El sujeto es hombre o mujer y tiene al menos 30 años.
    2. Si el sujeto es mujer no debe estar embarazada ni en periodo de lactancia. Una mujer en edad fértil debe documentar una prueba de embarazo negativa en el momento de la selección.
    NOTA: Se considera que una mujer está en edad fértil salvo si es posmenopáusica (amenorrea durante al menos 2 años) o si documenta esterilidad quirúrgica (ligadura tubárica bilateral o histerectomía total). Se puede admitir la participación de una mujer en el estudio en función a una prueba de embarazo en orina negativa. Si la prueba de la gonadotropina coriónica humana β (beta human chorionic gonadotropin, bBhCG) en orina es positiva, se debe realizar una prueba de bhCG en suero. Se debe confirmar que la prueba de embarazo sea negativa para participar en este estudio.
    3. Durante el estudio y durante 30 días después de recibir la última dosis de fármaco del estudio, las mujeres en edad fértil o los hombres capaces de engendrar hijos deben aceptar el uso de métodos anticonceptivos altamente efectivos (tasa de fracasos < 1 % cuando se usan de forma constante y correcta) o comprometerse a abstenerse de mantener relaciones sexuales. (Consulte el apartado 4.3).
    4. El sujeto debe cumplir los criterios diagnósticos de nOH, en base a una reducción mantenida en la TA ≥20 mmHg (sistólica) o ≥10 mmHg (diastólica) en un plazo de 3 minutos después de una inclinación ≥60o desde una posición supina, según lo determine la prueba de la mesa inclinada.
    5. El sujeto debe tener al menos una puntuación de 4 en OHSA#1 en la V1.
    6. Solo para los sujetos con EP: El sujeto presenta un diagnóstico de EP de acuerdo con los criterios del Banco de cerebros de la Sociedad de la Enfermedad de Parkinson del Reino Unido (United Kingdom Parkinson’s Disease Society Brain Bank) (1992).
    7. Solo para los sujetos con AMS: El sujeto presenta un diagnóstico de AMS posible o probable del subtipo parkinsoniano (AMS-p) o del subtipo cerebral (AMS-c), de acuerdo con los criterios de Gilman (2008).
    8. Solo para los sujetos con FAP: El sujeto presenta insuficiencia de los reflejos autonómicos, según lo determinado por la ausencia de exceso de TA en fase IV después de la maniobra de Valsalva.
    9. El sujeto presenta niveles de NE plasmática ≥ 100 pg/mL después de estar sentado durante 30 minutos.
    10. El sujeto está capacitado y dispuesto para otorgar un consentimiento informado por escrito firmado y fechado para participar antes del inicio de cualquier procedimiento relacionado con el estudio.
    11. El sujeto es capaz de comunicarse correctamente con el investigador y comprender al personal clínico, entiende las expectativas del estudio y puede cumplir los procedimientos, requisitos y restricciones del mismo.
    E.4Principal exclusion criteria
    Exclusion Criteria (For 0169 Completers Group):
    1. Subject may not be enrolled in another clinical trial (other than exiting Study 0169).
    2. Subject has psychiatric, neurological, or behavioral disorders that may interfere with the ability of subjects to give informed consent, or interfere with the conduct of the study.
    3. Medical, laboratory, or surgical issues deemed by the investigator to be clinically significant.
    4. Uncooperative attitude or reasonable likelihood of non-compliance with the protocol.
    5. Subject has a concurrent disease or condition that, in the opinion of the investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or pharmacokinetics of the study drug.

    Exclusion Criteria (For De Novo Group):
    1. Subject has a known systemic illness known to produce autonomic neuropathy, including, but not limited to, diabetes mellitus, diabetes insipidus, diabetic neuropathy, amyloidosis, or autoimmune neuropathies.
    2. Subject has a known intolerance to other NRIs or serotonin norepinephrine reuptake inhibitors (SNRIs).
    3. Subject currently uses concomitant antihypertensive medication for the treatment of essential hypertension.
    4. Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, whichever is longer, prior to V1 or requires concomitant use until the follow-up visit.
    5. Subject has changed dose, frequency, or type of prescribed medication for orthostatic hypotension within 7 days prior to V1.
    • Midodrine and droxidopa must be tapered off at least 7 days prior to V1.
    6. Subject has known or suspected alcohol or substance abuse within the past 12 months
    (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR®] definition of alcohol or substance abuse).
    7. Subject has a clinically unstable coronary artery disease, or has had a major cardiovascular or neurological event in the past 6 months.
    8. Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to V1.
    9. Subject has a history of untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk to the subject.
    10. Subject has any significant uncontrolled cardiac arrhythmia.
    11. Subject has a Montreal Cognitive Assessment (MoCA) ≤23.
    12. Subject is unable or unwilling to complete all protocol specified procedures including questionnaires.
    13. Subject had a myocardial infarction in the past 6 months or has current unstable angina.
    14. Subject has known congestive heart failure (New York Heart Association [NYHA]
    Class 3 or 4).
    15. Subject has had any malignant disease, other than carcinoma in situ of the cervix or basal cell carcinoma, within the past 2 years prior to screening.
    16. Subject has a known gastrointestinal (GI) condition, which in the investigator’s judgment, may affect the absorption of study medication (e.g., ulcerative colitis, gastric bypass).
    17. Subject has psychiatric, neurological, or behavioral disorders that may interfere with the ability of the subject to give informed consent, or interfere with the conduct of the study.
    18. Subject is currently receiving any investigational drug or has received an investigational drug within 30 days of dosing. An investigational drug is defined as drug that is not approved by a regulatory agency (e.g., Food and Drug Administration [FDA]).
    19. Subject has a clinically significant abnormal laboratory finding (e.g., alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3.0 x upper limit of normal [ULN]; blood bilirubin [total] >1.5 x ULN; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, or any abnormal laboratory value that could interfere with safety of the subject).
    20. Subject has demonstrated a history of lifetime suicidal ideation and/or suicidal behavior, as outlined by the C-SSRS (Baseline/Screening Version). Subject should be assessed by the rater for risk of suicide and the subject’s appropriateness for inclusion in the study.
    21. Subject has a concurrent disease or condition that, in the opinion of the investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or pharmacokinetics of the study drug.
    Criterios de exclusión (para el Grupo que completó 0169):
    1. El sujeto no puede estar inscrito en otro ensayo clínico (aparte del Estudio 0169 existente).
    2. El sujeto padece trastornos del comportamiento, neurológicos o psiquiátricos que pueden interferir en la capacidad del sujeto para otorgar su consentimiento informado o en la realización del estudio.
    3. Cuestiones médicas, analíticas o quirúrgicas consideradas por el investigador como clínicamente significativas.
    4. Actitud no cooperativa o probabilidad razonable de incumplimiento del protocolo.
    5. El sujeto tiene una afección o enfermedad concurrente que, en opinión del investigador, confundiría o interferiría con su participación en el estudio o la evaluación de la seguridad, la tolerabilidad o la farmacocinética del fármaco del estudio.

    Criterios de exclusión (para el Grupo de Novo):
    1. El sujeto padece una enfermedad sistémica que se sabe que produce una neuropatía autonómica, incluidas, entre otras, diabetes mellitus, diabetes insípida, neuropatía diabética, amiloidosis o neuropatías autoinmunes.
    2. El sujeto tiene intolerancia conocida a otros IRN o a los inhibidores de la recaptación de serotonina-norepinefrina (IRSN).
    3. El sujeto está tomando actualmente medicamentos antihipertensivos concomitantes para el tratamiento de la hipertensión esencial.
    4. El sujeto ha utilizado inductores o inhibidores de CYP1A2 potentes en un periodo de 7 días o 5 semividas, lo que sea mayor, antes de la V1 o requiere su uso concomitante hasta la visita de seguimiento.
    5. El sujeto ha cambiado la dosis, la frecuencia o el tipo de medicación recetada para la hipotensión ortostática dentro de los 7 días anteriores a la V1.
    • La ingesta de midodrina y droxidopa se debe reducir al menos 7 días antes de la V1.
    6. Se sospecha o conoce que el sujeto ha consumido alcohol o drogas durante los últimos 12 meses (definición de consumo de drogas o alcohol del Manual diagnóstico y estadístico de los trastornos mentales, 4.ª edición, texto revisado [DSM-IV-TR®]).
    7. El sujeto padece una arteriopatía coronaria clínicamente inestable o ha padecido un acontecimiento neurológico o cardiovascular grave durante los últimos 6 meses.
    8. El sujeto ha utilizado un inhibidor de la monoaminooxidasa (monoamine oxidase inhibitor, MAO-I) en un plazo de 14 días antes de la V1.
    9. El sujeto tiene antecedentes de glaucoma de ángulo cerrado tratado o sin tratar que según un oftalmólogo pueda provocar un riesgo elevado para el sujeto.
    10. El sujeto padece arritmia cardíaca no controlada.
    11. El sujeto presenta una evaluación cognitiva de Montreal (Montreal Cognitive Assessment, MoCA) ≤23.
    12. El sujeto no está capacitado ni dispuesto a completar todos los procedimientos especificados en el protocolo, incluidos los cuestionarios.
    13. El sujeto ha sufrido un infarto de miocardio en los últimos 6 meses o padece actualmente una angina inestable.
    14. El sujeto padece una insuficiencia cardíaca congestiva conocida (de clase 3 o 4, según la Asociación de Cardiología de Nueva York [New York Heart Association, NYHA]).
    15. El sujeto ha padecido cualquier enfermedad maligna que no sea un carcinoma localizado en el cuello uterino o un carcinoma basocelular en un periodo de 2 años antes de la selección.
    16. El sujeto padece una enfermedad gastrointestinal (GI) que, a juicio del investigador, puede afectar a la absorción del medicamento del estudio (por ejemplo, colitis ulcerosa o derivación gástrica).
    17. El sujeto padece trastornos del comportamiento, neurológicos o psiquiátricos que pueden interferir en la capacidad del sujeto para otorgar su consentimiento informado o en la realización del estudio.
    18. El sujeto está recibiendo actualmente algún fármaco en investigación o lo ha recibido durante un plazo de 30 días. Un fármaco en investigación se define como un fármaco no aprobado por una agencia reguladora (por ejemplo, la Administración de Alimentos y Medicamentos estadounidense, FDA).
    19. El sujeto presenta una anomalía clínicamente significativa en los resultados analíticos, (por ejemplo, alanina aminotransferasa [ALT] o aspartato aminotransferasa [AST] >3 x límite superior de la normalidad [LSN], bilirrubina en sangre [total] >1,5 x LSN, tasa de filtración glomerular estimada [TFGe] <30 ml/min/1,73m2 o cualquier valor analítico anómalo que pudiera interferir en la seguridad del sujeto).
    20. El paciente posee antecedentes de pensamientos suicidas y/o comportamiento suicida a lo largo de la vida, según se indica en la C-SSRS (versión Inicio/Selección). El evaluador debe evaluar el riesgo de suicidio y la adecuación del sujeto para su inclusión en el estudio.
    21. El sujeto tiene una afección o enfermedad concurrente que, en opinión del investigador, confundiría o interferiría con su participación en el estudio o la evaluación de la seguridad, la tolerabilidad o la farmacocinética del fármaco del estudio
    E.5 End points
    E.5.1Primary end point(s)
    The primary study endpoint is the proportion of treatment failure at Week 6 during the double-blind randomized withdrawal phase. Treatment failure is defined as subjects who meet the following criteria at Week 6 following randomization (V9, D155):

    Change (worsening) from baseline in OHSA#1 score of 1.0 point and worsening of disease severity as assessed by a 1 point change in PGI-S.
    El criterio de valoración principal del estudio es la proporción de fracaso del tratamiento en la Semana 6 durante la fase de retirada aleatorizada doble ciego. El fracaso del tratamiento se define como los sujetos que cumplan los siguientes criterios en la Semana 6 tras la aleatorización (V9, D155):

    Cambio (empeoramiento) respecto al inicio en la puntuación de OHSA#1 de 1,0 punto y empeoramiento de la gravedad de la enfermedad evaluada por un cambio de 1 punto en PGI-S.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 6 following randomization (Visit 9, Day 155)
    Semana 6 después de la aleatorización (V9, D155)
    E.5.2Secondary end point(s)
    • Change from baseline in OHSA#1 at Week 6 post randomization (V9, D155)
    • Change from baseline in OHSA composite score at Week 6 post randomization (V9, D155)
    • Change from baseline in OHDAS composite score at Week 6 post randomization (V9, D155)
    • Standing SBP during orthostatic standing test at Week 6 post randomization (V9, D155)
    • Change from baseline in percent of time spent in supine, sitting, and standing position as measured by a wearable device at Week 6 post randomization (V9, D155)

    Additional secondary endpoints by disease type include:
    For subjects with PD
    • Change from baseline in UPDRS at Week 6 post randomization (V9, D155)
    • Change from baseline in PDQ-8 at Week 6 post randomization (V9, D155)

    For subjects with MSA
    • Change from baseline in UMSARS at Week 6 post randomization (V9, D155)
    • Change from baseline in COMPASS-31 at Week 6 post randomization (V9, D155)
    Other efficacy endpoints are:
    • Change from baseline in OHQ overall composite score at Week 6 post randomization (V9, D155)
    • Change from baseline in EQ-5D-5L at Week 6 post randomization (V9, D155)
    • NMSS at Week 6 post randomization (V9, D155)
    • HADS at Week 6 post randomization (V9, D155)
    • BSFC-s at Week 6 post randomization (V9, D155)
    • Cambio con respecto al inicio en OHSA#1 en la Semana 6 después de la aleatorización (V9, D155)
    • Cambio con respecto al inicio en la puntuación compuesta de OSHA en la Semana 6 después de la aleatorización (V9, D155)
    • Cambio con respecto al inicio en la puntuación compuesta de OHDAS en la Semana 6 después de la aleatorización (V9, D155)
    • TAS en bipedestación durante la prueba de posición ortostática en la Semana 6 después de la aleatorización (V9, D155)
    • Cambio con respecto al inicio en el porcentaje de tiempo que pasa en posición supina, sentado y de pie, medido mediante un dispositivo portátil en la Semana 6 después de la aleatorización (V9, D155)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 6 post randomization (Visit 9, Day 155)
    Semana 6 después de la aleatorización (V9, D155)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others 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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Randomized withdrawal study
    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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Australia
    Austria
    Bulgaria
    Canada
    Denmark
    Estonia
    France
    Germany
    Hungary
    Israel
    Italy
    New Zealand
    Poland
    Russian Federation
    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
    End of trial is LPLV for those who choose not to continue in Study 171.
    El final del estudio es la última visita del último paciente para aquellos que decidan no continuar con el estudio 171.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months4
    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: 140
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 118
    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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 258
    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)
    Subjects completing the 6-week double-blind treatment period will be eligible to enroll and continue receiving study medication in study 0171 (0171 is an Open Label, long term safety study).
    Los sujetos que completen el periodo de tratamiento doble ciego de 6 semanas serán aptos para ser incluidos en el estudio 0171 y continuar recibiendo la medicación del ensayo (0171 es un ensayo abierto de seguridad a largo plazo).
    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 Decision2019-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-11
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-10-31
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