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    Summary
    EudraCT Number:2019-001598-10
    Sponsor's Protocol Code Number:PB1046-PT-CL-0004
    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:2019-12-20
    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 number2019-001598-10
    A.3Full title of the trial
    A Randomized, Double-Blind, Parallel Group, Phase 2 Study to Assess the Safety, Tolerability, and Efficacy of Once Weekly Subcutaneous Injections of a Sustained-Release VIP Analogue, PB1046, in Adult Subjects with Symptomatic Pulmonary Arterial Hypertension
    Estudio de fase 2 aleatorizado, de grupos paralelos, doble ciego para evaluar la seguridad, tolerabilidad y eficacia de las inyecciones subcutáneas semanales de
    un análogo de VIP de liberación sostenida, PB1046, en sujetos adultos con hipertensión arterial pulmonar sintomática
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 Study to Assess Safety, Tolerability and Efficacy of Once Weekly Subcutaneous Injections of PB1046 (study drug) in Subjects With Symptomatic Pulmonary Arterial Hypertension
    Estudio fase 2 para evaluar la seguridad, tolerabilidad y eficacia de inyecciones subcutáneas de PF1046 (medicamento del estudio) una vez a la semana en sujetos con hipertensión arterial pulmonar sintomática
    A.4.1Sponsor's protocol code numberPB1046-PT-CL-0004
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03556020
    A.5.4Other Identifiers
    Name:US IND NumberNumber:135,417
    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 SponsorPhaseBio Pharmaceuticals, 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 supportPhaseBio Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPhaseBio Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointPB1046 Clinical Project Manager
    B.5.3 Address:
    B.5.3.1Street Address1 Great Valley Parkway, Suite 30
    B.5.3.2Town/ cityMalvern
    B.5.3.3Post codePA 19355
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34932275779
    B.5.5Fax number+1610981-6520
    B.5.6E-mailPB1046clinicaltrials@phasebio.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVasomera (PB1046) Injection
    D.3.2Product code PB1046
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot available
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codePB1046
    D.3.9.3Other descriptive namePB1046, VIP-ELP1-120, Vasomera
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Symptomatic Pulmonary Arterial Hypertension
    Hipertensión arterial pulmonar sintomática
    E.1.1.1Medical condition in easily understood language
    PAH is a progressive and life-threatening disease which is characterized by high blood pressure in the lungs caused by abnormal constriction and remodeling of the arteries in the lungs.
    La HAP es una enfermedad progresiva y potencialmente mortal caracterizada por presión arterial alta en los pulmones por la constricción anormal y la remodelación de las arterias en los pulmones
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assess the safety, tolerability, and effect on pulmonary vascular resistance (PVR) of dose titrated levels of PB1046 administered subcutaneously once-weekly for 16 weeks in subjects with symptomatic pulmonary arterial hypertension (PAH)
    Evaluar la seguridad, la tolerabilidad y el efecto en la resistencia vascular pulmonar (RVP) de PB1046 en niveles de ajuste de dosis, administrados semanalmente en forma subcutánea durante 16 semanas en sujetos con hipertensión arterial pulmonar (HTP) sintomática.
    E.2.2Secondary objectives of the trial
    • To investigate the effect of PB1046 on exercise capacity following treatment in PAH subjects
    • To investigate the effect of PB1046 on change in N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP)
    • To investigate the effect of PB1046 on cardiopulmonary hemodynamics
    • To evaluate the multi-dose pharmacokinetic profile of individually dose-titrated PB1046 administered once-weekly for 16 weeks
    • To evaluate the immunogenicity profile of PB1046 PAH subjects
    • Investigar el efecto en la capacidad de ejercicio después del tratamiento con PB1046 en sujetos con HTP.
    • Investigar el efecto de PB1046 sobre el cambio en el fragmento terminal N del péptido natriurético cerebral prohormona (NT-proBNP).
    • Investigar el efecto de PB1046 en la hemodinámica cardiopulmonar.
    • Evaluar el perfil de farmacocinética (PK) de múltiples dosis de PB1046 con ajuste de dosis administrado una vez por semana durante 16 semanas.
    • Evaluar el perfil de inmunogenicidad de PB1046 en sujetos con HTP.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects will be eligible for inclusion in the study if they meet all the following criteria at screening and up to the time of first dose as indicated:
    1. Male and female subjects with PAH, > or =18 and < or = 79 years of age, who are symptomatic and have reduced exercise capacity due primarily to their PAH diagnosis and have been assessed by a qualified individual (i.e. physician, physician assistant, nurse practitioner) to be in NYHA/WHO functional class II or III
    2. Willing and able to sign a written informed consent prior to all study-related procedures
    3. Subjects with PAH belonging to one of the following subgroups of the NICE Clinical Classification of Pulmonary Hypertension Group 1:
    a. Idiopathic
    b. Heritable
    c. Drug or toxin-induced
    d. Associated with connective tissue disease, HIV infection, portal hypertension, congenital heart disease (pulmonary-to-systemic shunt, e.g., atrial septal defect (ASD) or patent ductus arteriosus (PDA), at least 1 year after surgical repair)
    4. Two 6MWT results > 50 m and < 550 m prior to randomization with results +/- 10% of each other. Note: Up to four tests may be conducted between Screening and Randomization for eligibility purposes (no more than two 6MWT may be performed on the same day, and must be completed at least two hours apart)
    5. Hemodynamic assessment of PAH by right heart catheterization (RHC) demonstrating elevated mPAP and PVR as indicated below during the Screening Period
    a. mPAP of > or = 25 mmHg; and
    b. PVR > or = 400 dyne•sec/cm5; and
    c. PCWP or left ventricular end diastolic pressure (LVEDP) of < or = 12 mmHg if PVR > or = 400 and < 500 dynes•sec/cm5; or PCWP/LVEDP < or = 15 mmHg if PVR > or = 500 dynes•sec/cm5
    6. Body mass index (BMI) > or = 18 kg/m2 and < or = 40 kg/m2 at screening
    7. Meet the following criteria determined by pulmonary function tests completed no more than 24 weeks prior to screening
    a. Forced expiratory volume in one second (FEV1) > or = 55% of predicted normal
    b. FEV1: FVC (forced vital capacity) ratio > or = 0.60
    8. Agrees to use a medically acceptable method of contraception (both male and female patients) throughout the entire study period and continuing for 30 days after their last dose of study drug if the possibility of conception exists. Medically acceptable methods of contraception include the following: abstinence (not having sex), vasectomy (with confirmed negative sperm counts), condoms and partner using vaginal spermicide and/or cervical cap with spermicide or sponge; oral, implantable, or injectable contraceptives (starting >2 months before dosing), diaphragm with vaginal spermicide, intrauterine device,, surgical sterilization (>6 months after surgery). Female subjects < 45 years of age of non-childbearing potential are defined as being surgically sterile by bilateral tubal ligation, bilateral oophorectomy, or hysterectomy. Female subject 45 to 60 years of age, inclusive, who is post-menopausal for at least 1 year and have a follicle-stimulating hormone (FSH) level confirmation indicating post-menopausal status, will be considered to be of non-childbearing potential. Female subjects >60 years of age are considered post-menopausal and of non-childbearing potential
    9. Stable background medical regimen of up to 3 PAH disease-specific therapies for at least 3 months comprised of any combination of oral and/or inhaled or IV therapy and at stable doses for at least 30 days prior to Screening
    10. If a subject has historical diagnosis (prior to screening visit) of being positive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV), must be clinically stable and if on therapy, must be on stable therapy for HIV or HCV for at least 3 months
    11. Willing and able to understand and follow instructions; return to the study unit for specified study visits; and able to participate in the study for the entire period
    Los sujetos serán elegibles para participar en el estudio si cumplen con los
    siguientes criterios:
    1. Sujetos masculinos y femeninos con HTP, > o = 18 y < o =79, que tengan síntomas o capacidad de ejercicio disminuida principalmente a causa de un diagnóstico de HTP y hayan sido evaluados por un individuo calificado (por ejemplo, médico, asistente médico o personal de enfermería calificado) como clase funcional II o III de la NYHA/OMS.
    2. Deben estar dispuestos y poder firmar un consentimiento informado por escrito antes de realizarse todos los procedimientos relacionados con el estudio.
    3. Sujetos con HTP que pertenezcan a uno de los siguientes subgrupos de la clasificación clínica de hipertensión pulmonar, grupo 1:
    a. Idiopático.
    b. Hereditario.
    c. Inducido por medicamentos o toxinas.
    d. Asociado con enfermedad del tejido conectivo, infección por VIH, hipertensión portal, enfermedad cardiaca congénita (derivación pulmonar a sistémica, por ejemplo, defecto septal auricular (ASD)
    o conducto arterioso persistente (PDA), al menos un año después de la reparación quirúrgica).
    4. Dos resultados de PM6M >50 m y <550 m antes de la aleatorización con resultados +/-10 % entre sí. Nota: Se pueden realizar hasta cuatro pruebas entre la selección y la aleatorización para fines de elegibilidad (no se pueden realizar más de dos PM6M el mismo día, y se deben terminar al menos con dos horas de diferencia).
    5. Evaluación hemodinámica de HTP por CCD que demuestre mPAP y RVP elevados, según se indica a continuación, durante el periodo de selección:
    a. mPAP de > o =25 mmHg; y
    b. RVP > o =400 dina s/cm 5 ; y
    c. PCWP o presión ventricular extrema diastólica izquierda (LVEDP) de < o =12 mmHg si RVP ≥400 y <500 dina s/cm 5 ; o PCWP/LVEDP < o =15 mmHg si RVP > o =500 dina s/cm 5 .
    6. Índice de masa corporal (IMC) > o =18 kg/m² y < o =40 kg/m² en la selección.
    7. Cumplimiento de los siguientes criterios determinados por pruebas de función pulmonar terminadas no más de 24 semanas antes de la selección.
    a. Capacidad espiratoria forzada en un segundo (FEV1) ≥55 % de predicción normal.
    b. FEV1: Proporción de FVC (capacidad vital forzada) > o = 0,60.
    8. Debe aceptar utilizar un método anticonceptivo médicamente aceptable (tanto pacientes hombres como mujeres) durante todo el periodo del estudio y continuar durante 30 días después de la última dosis del medicamento del estudio si existe posibilidad de concepción. Los métodos anticonceptivos médicamente aceptables incluyen abstinencia (no tener sexo), vasectomía (con recuento de esperma negativo confirmado), preservativos y uso de espermicida vaginal o capuchón cervical con espermicida o esponja; anticonceptivos orales, implantables o inyectables (a partir de >2 meses antes de la dosis), diafragma con espermicida vaginal, dispositivo intrauterino, esterilización quirúrgica (>6 meses después de la cirugía). Los sujetos femeninos <45 años sin potencial de capacidad reproductiva se definen como estériles quirúrgicamente por oclusión tubárica bilateral, ovariectomía bilateral o histerectomía. Los sujetos femeninos de 45 a 60 años inclusive, que hayan sido posmenopáusicas durante al menos un año y tengan una confirmación del nivel de hormona estimuladora de folículos (FSH) que indique estado posmenopáusico se considerarán sin potencial de capacidad reproductiva. Los sujetos femeninos >60 años se consideran posmenopáusicos y sin potencial de capacidad reproductiva.
    9. Régimen médico previo estable de tres (3) tratamientos específicos para la enfermedad de HTP durante al menos tres (3) meses, que consistan en cualquier combinación de tratamiento oral, por inhalación o intravenoso en dosis estables durante al menos 30 días antes de la selección.
    10. Si un sujeto tiene un diagnóstico histórico (antes de la visita de selección) positivo de virus de inmunodeficiencia humana (VIH), antígeno de superficie de hepatitis B (HBsAg) o virus de hepatitis C (HCV), debe estar clínicamente estable y, si está en tratamiento, debe haber estado en tratamiento estable para VIH o HCV durante al menos tres (3) meses.
    11. Debe estar dispuesto y poder comprender y seguir instrucciones; volver a la unidad del estudio para las visitas del estudio especificadas, y poder participar en el estudio durante todo el periodo.
    E.4Principal exclusion criteria
    Subjects will be excluded from the study if they meet any of the following criteria:
    1. Concomitant medical disorder, condition, or history, that in the opinion of the Investigator would impair the subject’s ability to participate in or complete the requirements of the study
    2. Concomitant medical disorder that is expected to limit the subject’s life-expectancy to < or = 1 year
    3. Pregnant or lactating female subjects
    4. First positive result from serology testing at Visit 1 (screening labs) for HIV, HBsAg, or HCV prior to randomization
    5. Participation in another investigational drug study within 30 days prior to screening or participating in a non-medication study which, in the opinion of the Investigator, would interfere with the study compliance or outcome assessments
    6. Use of subcutaneous prostanoid/prostacyclin therapy for PAH within 30 days prior to the screening visit
    7. More than mild mitral or aortic valve disease, left ventricular ejection fraction < 50%, or left ventricular regional wall motion abnormality suggestive of active coronary artery disease on documented 2D-echocardiography occurring within 12 months of Screening
    8. Sustained SBP < 95 mmHg and/or diastolic blood pressure (DBP) < 50 mmHg (confirmed by a duplicate seated reading) on at least 3 consecutive readings (self-monitored or office) at screening and prior to dosing, or overt symptomatic hypotension
    9. Sustained resting heart rate >110 beats per minute (BPM) (confirmed by duplicate assessments of office vital signs or consecutive ECG assessments) on at least 3 consecutive readings at screening and prior to dosing
    10. Clinically significant renal dysfunction based on Screening labs as measured by the estimated glomerular filtration rate (eGFR) of < 30 mL/min/1.73m2 as calculated by the IDMS-Traceable MDRD equation: eGFR = (mL/min/1.73 m2) = 175 x (serum creatinine in mg/dL) – 1.154 x (Age) – 0.203 x (0.742 if female) x (1.212 if African American) (conventional units)
    11. Significant liver dysfunction as measured by any one of the following at screening:
    a. alanine aminotransferase (ALT) >3.0 times ULN or
    b. aspartate aminotransferase (AST) >3.0 times ULN or
    c. serum bilirubin > or = 1.6 mg/dL
    12. Known history of substance abuse within the past 1 year that in the opinion of the Investigator would impair the subject’s ability to participate in or complete the requirements of the study
    13. Any major surgical procedure within 90 days prior to screening or planned surgical procedure during the study period
    14. Any in-patient hospitalization (defined as greater than 23 hours) within 30 days of subject screening
    15. Enrollment within the past 3 months prior to screening or plans to enroll during the study into a cardiopulmonary rehabilitation program
    16. Other medical or psychiatric condition which, in the opinion of the Investigator, would place the subject at increased risk or would preclude obtaining voluntary consent or would confound the objectives of study
    17. Known hypersensitivity to study drug or any of the excipients of the drug formulation;
    18. Three or more of the following:
    a. BMI >35
    b. Current atrial fibrillation
    c. Current Diabetes Mellitus
    d. Current Hypertension
    e. History of clinically significant coronary artery disease in prior 3 years
    Los sujetos serán excluidos del estudio si cumplen con los siguientes criterios:
    1. Desorden, condición o historial médico concomitante, que en opinión del investigador pudiera afectar la capacidad del sujeto para participar o completar los requerimientos del estudio.
    2. Desorden médico concomitante con expectativa de vida del sujeto < o = 1 año.
    3. Mujeres embarazadas o en periodo de lactancia.
    4. Primer resultado positivo de la prueba de serología en la visita 1 (análisis de laboratorio iniciales) para VIH, HBsAg o HCV antes de la aleatorización.
    5. Participación en otro estudio de medicamento en fase de investigación dentro de los 30 días anteriores a la selección o participación en un estudio sin medicación que, en opinión del investigador, pudiera interferir con el cumplimiento del estudio o las evaluaciones de los resultados.
    6. Uso de tratamiento con prostanoide/prostaciclina para HTP dentro de los 30 días anteriores a la visita de selección.
    7. Enfermedad de la válvula aórtica o mitral más que leve, fracción de eyección del ventrículo < 50 % o anormalidad de movimiento de la pared regional ventricular indicativo de enfermedad de las arterias coronarias activa en ecocardiografía 2D documentada, ocurrente dentro de los 12 meses a partir de la selección.
    8. Presión arterial sistólica (PAS) sostenida <95 mmHg o presión arterial diastólica (PAD) <50 mmHg (confirmado por una lectura asentada por duplicado) en al menos tres (3) lecturas consecutivas (automonitoreadas o en consultorio) en la selección y antes de la dosis, o hipotensión sintomática evidente.
    9. Frecuencia cardiaca en descanso sostenida >110 latidos por minuto (bpm) (confirmada por evaluaciones por duplicado de signos vitales en el consultorio o evaluaciones de ECG consecutivas) al menos en tres (3) lecturas consecutivas en la selección o antes de la dosis.
    10. Disfunción renal clínicamente significativa basada en los laboratorios de selección, medida por la tasa de filtración glomerular estimada (eGFR) de <30 mL/min/1,73 m² calculada por la ecuación IDMS-MDRD trazable: eGFR = (mL/min/1,73 m²) = 175 x (creatinina sérica en mg/dL) - 1,154 x (edad) - 0,203 x (0,742 si es mujer) x (1,212 si es afroamericano) (unidades convencionales).
    11. Disfunción hepática significativa, medida por cualquiera de los siguientes factores en el momento de la selección:
    a. alanina aminotransferasa (ALT) >3,0 veces ULN o
    b. aspartato aminotransferasa (ALT) >3,0 veces ULN o
    c. bilirrubina sérica > o = 1,6 mg/dL.
    12. Antecedentes conocidos de abuso de sustancias dentro del último año que, en opinión del investigador, pudieran afectar la capacidad del sujeto para participar o completar los requerimientos del estudio.
    13. Cualquier cirugía mayor dentro de los noventa (90) días anteriores a la selección o el procedimiento quirúrgico planificado durante el periodo de estudio.
    14. Cualquier hospitalización (definida como mayor de 23 horas) dentro de los 30 días después de la selección del sujeto.
    15. Inscripción dentro de los últimos tres (3) meses anteriores a la selección, o intención de inscribirse en un programa de rehabilitación cardiopulmonar durante el estudio.
    16. Otra afección médica o psiquiátrica que, en opinión del investigador, pudiera exponer al sujeto a un mayor riesgo o impedir la obtención del consentimiento voluntario o confundir los objetivos de estudio.
    17. Hipersensibilidad conocida al medicamento del estudio o a cualquiera de los excipientes de la formulación del medicamento.
    18. Tres o más de los siguientes:
    a. IMC >35.
    b. Fibrilación auricular actual.
    c. Diabetes mellitus actual.
    d. Hipertensión actual.
    e. Antecedentes de enfermedad de las arterias coronarias clínicamente significativa en los últimos 3 años.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint:
    Change from Baseline to end of assessment in Pulmonary Vascular Resistance (PVR)
    Cambio en RVP desde el periodo inicial hasta el final de la evaluación.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Right Heart Catherization (RHC) performed between Screening and Baseline and between Visits 17 (End of Treatment) and 18, preferably 48 to 72 hours after the last dose.
    La cateterización cardíaca derecha (RHC) se realizó entre la visita de selección y la basal y entre las visitas 17 (fin del tratamiento) y 18, preferiblemente de 48 a 72 horas después de la última dosis.
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints:
    1. Change from Baseline to end of assessment in:
    • Six Minute Walk Test (6MWT)
    • NT-proBNP
    • Cardiac index (CI), mean pulmonary artery pressure (mPAP), mean right atrial pressure (mRAP), pulmonary capillary wedge pressure (PCWP), mixed venous oxygen saturation (SvO2), including pulmonary artery compliance

    2. Safety Endpoints
    • Incidence and severity of AEs and their relationship to study drug
    • Vital signs, laboratory parameters, electrocardiograms (ECGs) and their relationship to PB1046
    • Immunogenicity

    3. Pharmacokinetic Endpoints:
    • Plasma PB1046 concentration at each time point and PK parameters
    Criterios secundarios de valoración de la eficacia:
    1, Cambio desde el periodo inicial hasta el final de la evaluación en:
    • Prueba de marcha de seis minutos (PM6M).
    • NT-proBNP.
    • Índice cardiaco (IC), presión arterial pulmonar media (mPAP), presión auricular derecha media (mRAP), presión de enclavamiento capilar pulmonar (PCWP), saturación de oxígeno venoso combinado (SvO2) y cumplimiento de arteria pulmonar.

    2. Criterios de valoración de seguridad:
    • Incidencia y severidad de los EA y su relación con el medicamento del estudio.
    • Signos vitales, parámetros de laboratorio, electrocardiogramas (ECG) y su relación con PB1046.
    • Inmunogenicidad.


    3. Criterios de valoración de farmacocinética:
    Concentración plasmática de PB1046 en cada punto temporal y parámetros PK.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. From Baseline (V2) to end of assessment (V18)
    2. From Baseline (V2) to the day of enrollment in the open-label extension (OLE) study PB1046-PT-CL-0006 (V18)
    or
    2. For those not opting to continue into the OLE, safety endpoints will continue to be collected for 28 days after the final dose of PB1046 (V18). Moreover, approximately 56 days after the final dose (V18) a blood sample will be also drawn for immunogenicity testing. If anti-drug antibodies are still present at 56 days post last dose, then subjects will be followed further until resolution of the antibody status.
    3. From Baseline to end of assessment
    1. Desde basal (V2) hasta el final de la evaluación (V18)
    2. Desde lbasal (V2) hasta el día de la incusión en el estudio de extensión abierta (OLE) PB1046-PT-CL-0006 (V18)
    o
    2. Para aquellos que no opten por continuar en el OLE, los criterios de valoración de seguridad se seguirán recogiendo durante 28 días después de la dosis final de PB1046 (V18). Además, aproximadamente 56 días después de la dosis final (V18) también se extraerá una muestra de sangre para la prueba de inmunogenicidad. Si los anticuerpos antimedicamento todavía están presentes a los 56 días después de la última dosis, se seguirá a los sujetos hasta que se resuelva el estado del anticuerpo.
    3. Desde basal hasta el final de la evaluación
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    immunogenicity
    Inmunogenicidad
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    búsqueda de dosis
    dose titration
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    diferentes esquemas de tratamiento del mismo medicamento en investigación
    different treatment schedule of the same IMP
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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
    Austria
    Belgium
    Bulgaria
    Czech Republic
    Germany
    Greece
    Hungary
    Italy
    Poland
    Romania
    Serbia
    Spain
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS - Visit 18 (Week 17)/End of Treatment Visit
    Última visita del último paciente - Visita 18 (semana 17) / Visita de fin de tratamiento
    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 months7
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days16
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 23
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 63
    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 can choose to enroll into an open label extension (OLE) study (protocol: PB1046-PT-CL-0006) after the end of treatment (EoT) visit. Subjects who do not enroll into the OLE, after the EoT will be monitored from safety point of view for 28 days after the final dose of PB1046. Moreover, approximately 56 days after the final dose, subjects will be also tested for immunogenicity. After that, they will be treated according to the available standard of care, as per treating physician decision.
    Los sujetos pueden participar en un estudio de extensión abierto (OLE) (protocolo PB1046-PT-CL-0006) después de la visita de fin de tratamiento (FdT). Los que no participen en el OLE serán monitorizados desde el punto de vista de seguridad durante 28 días tras la última dosis de PB1046 y, unos 56 días tras la dosis final, se someterán a pruebas de inmunogenicidad. Después de eso, serán tratados de acuerdo con el estándar de atención disponible, según la decisión su médico
    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 Decision2020-02-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-26
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-12-22
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