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    Summary
    EudraCT Number:2018-002796-18
    Sponsor's Protocol Code Number:BIA-51058-202
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-16
    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 number2018-002796-18
    A.3Full title of the trial
    An open-label, multicentre study to evaluate the safety and efficacy of zamicastat as adjunctive therapy in long-term treatment of pulmonary arterial hypertension (PAH) disease
    Un estudio abierto y multicéntrico para evaluar la seguridad y eficacia del zamicastat como terapia adyuvante en el tratamiento a largo plazo de la hipertensión arterial pulmonar (HAP)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    To study the safety and effectiveness of the maximum tolerated dose of zamicastat, found in BIA-51058-201, in the treatment of long-term PAH.
    Estudiar la seguridad y eficacia de la máxima dosis tolerada del zamicastat, basado en BIA-51058-201, en el tratamiento a largo plazo de la HAP.
    A.4.1Sponsor's protocol code numberBIA-51058-202
    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 SponsorBial - Portela & Ca, S.A.
    B.1.3.4CountryPortugal
    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 supportBial - Portela & Ca, S.A.
    B.4.2CountryPortugal
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHospital 12 de Octubre Servicio de Cardiología
    B.5.2Functional name of contact pointPilar Escribano-Subías
    B.5.3 Address:
    B.5.3.1Street AddressAv. Cordoba, s/n, 28041
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28041
    B.5.3.4CountrySpain
    B.5.4Telephone number+34917792472
    B.5.6E-mailpilar.escribano.subias@gmail.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 nameZamicastat
    D.3.2Product code BIA-5-1058
    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 INNZAMICASTAT
    D.3.9.1CAS number 1080028-80-3
    D.3.9.2Current sponsor codeBIA 5-1058
    D.3.9.3Other descriptive nameBIA 5-1058
    D.3.9.4EV Substance CodeSUB192395
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pulmonary arterial hypertension
    Hipertensión arterial pulmonar
    E.1.1.1Medical condition in easily understood language
    Pulmonary arterial hypertension
    Hipertensión arterial pulmonar
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to assess the safety and tolerability of the maximum tolerated zamicastat doses, achieved in the study BIA-51058-201, during long-term treatment in PAH disease.
    El objetivo primario de este estudio es evaluar la seguridad y la tolerabilidad de las dosis máximas toleradas de zamicastat, alcanzadas en el estudio BIA-51058-201, durante el tratamiento a largo plazo de la enfermedad HAP.
    E.2.2Secondary objectives of the trial
    To assess further efficacy, safety and tolerability parameters of the maximum tolerated zamicastat doses in long-term treatment of PAH.
    Evaluar parámetros adicionales de eficacia, seguridad y tolerabilidad de las dosis máximas toleradas de zamicastat, durante el tratamiento a largo plazo de la enfermedad HAP.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Have completed MPV3 of the preceding study BIA-51058-201.
    2. Able to comprehend and willing to sign an informed consent form
    1. Haber completado la MPV3 del estudio anterior BIA-51058-201.
    2. Capaces de comprender y dispuestos a firmar un formulario de consentimiento informado.
    E.4Principal exclusion criteria
    1. Significant non-compliance with the protocol during the preceding study BIA-51058-201 which may have an impact on this extension study.
    2. WHO functional class IV as judged by the investigator.
    3. Persistent hypotension defined as systolic blood pressure (SBP) < 95 mmHg or diastolic blood pressure (DBP) < 50 mmHg.
    4. Uncontrolled diabetes mellitus.
    5. Occurrence of an AE during the preceding study which is judged by the investigator as contraindicative to further participation in the extension study.
    6. Any disease known to cause pulmonary hypertension other than PAH WHO Group 1, e.g. obstructive lung diseases, parasitic disease affecting the pulmonary system, sickle cell anaemia, left heart disease.
    7. History of moderate to severe hepatic impairment (Child-Pugh B and C).
    8. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (measured at V1).
    9. Use of the following prohibited medication or treatments during study participation:
    calcium channel blockers (CCBs) if used for the treatment of PAH in vasoreactive patients; drugs containing a catechol group that is metabolised by DβH (e.g. rimiterole, isoprenaline, dopamine, dopexamine or dobutamide) or α- and/or β-blockers.
    10. Presence of any other significant or progressive/unstable medical condition that, in the opinion of the investigator, would compromise evaluation of the study treatment or may jeopardise the patient’s safety, compliance or adherence to protocol requirements.
    11. For women: Pregnancy or breast-feeding. Women of childbearing potential unable or unwilling to undergo pregnancy tests and practice acceptable contraceptive measures. Acceptable methods for women are surgical intervention (e.g. bilateral tubal occlusion), intrauterine device, double-barrier methods and true sexual abstinence (i.e. when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    12. Concurrent participation in any other drug investigational study, except BIA-51058-201.
    13. Vulnerable patients according to Section 1.61 of the ICH guideline for Good Clinical Practice E6.
    1. Incumplimiento significativo del protocolo durante el estudio anterior BIA-51058-201 que pueda tener un impacto en este estudio de extensión.
    2. Clase funcional IV de la OMS, a juicio del investigador.
    3. Hipotensión persistente definida como tensión arterial sistólica (PAS) <95 mmHg o tensión arterial diastólica (PAD) <50 mmHg.
    4. Diabetes mellitus no controlada.
    5. Ocurrencia de un acontecimiento adverso durante el estudio anterior que el investigador considera como contraindicación para seguir participando en el estudio de extensión.
    6. Cualquier enfermedad que se sepa que causa hipertensión pulmonar diferente de la HAP grupo 1 de la OMS, como, por ejemplo, enfermedades pulmonares obstructivas, enfermedad parasitaria que afecte al sistema pulmonar, anemia de células falciformes, síndrome del corazón izquierdo.
    7. Historial de insuficiencia hepática de moderada a grave (Child-Pugh B y C).
    8. Velocidad de filtración glomerular estimada (VFGe) <30 ml/min/1,73 m2 (medida en la V1).
    9. Uso de las siguientes medicaciones o tratamientos prohibidos durante la participación en el estudio: bloqueadores de los canales de calcio (BCC) si se usan para el tratamiento de la HAP en pacientes vasorreactivos; fármacos que contienen un grupo catecol que se metaboliza por DβH (por ejemplo, rimiterol, isoprenalina, dopamina, dopexamina o dobutamina) o alfabloqueantes y/o betabloqueantes.
    10. Presencia de cualquier afección médica inestable/progresiva o significativa que, en opinión del investigador, pueda comprometer la evaluación del tratamiento del estudio o pueda poner en peligro la seguridad del paciente, el cumplimiento o el seguimiento de los requisitos del protocolo.
    11. Para mujeres: Embarazo o lactancia. Las mujeres en edad fértil que no pueden o no desean someterse a pruebas de embarazo y a la aplicación de medidas anticonceptivas admisibles. Los métodos admisibles para las mujeres son la intervención quirúrgica (p. ej., ligadura de trompas bilateral), el dispositivo intrauterino, los métodos de barrera doble y la abstinencia sexual efectiva (es decir, cuando esta se ajusta al estilo de vida normal y de preferencia de la paciente). La abstinencia periódica (p. ej., método del calendario, de la temperatura, de la post-ovulación) y el método de marcha atrás no son métodos anticonceptivos admisibles.
    12. Participación simultánea en cualquier otro estudio con fármacos en fase de investigación clínica, a excepción del BIA-51058-201.
    13. Pacientes vulnerables de acuerdo con la Sección 1.61 de la directriz de la ICH sobre Buenas Prácticas Clínicas E6.
    E.5 End points
    E.5.1Primary end point(s)
    The safety and tolerability of the used zamicastat doses will be evaluated by:
    1. Adverse events
    2. Clinically relevant changes in laboratory parameters (haematology, biochemistry, urinalysis)
    3. Clinically relevant changes in vital signs
    4. Clinically relevant changes in ECG parameters
    5. Incidence of new scars (only in patients with scleroderma)
    6. Skin score (only in patients with scleroderma)
    La seguridad y la tolerabilidad de las dosis de zamicastat utilizadas se van a evaluar en función de:
    1. Eventos adversos
    2. Cambios clínicamente relevantes en los parámetros de laboratorio (hematología, bioquímica, análisis de orina)
    3. Cambios clínicamente relevantes en las Constantes vitales
    4. Cambios clínicamente relevantes en el electrocardiograma
    5. Incidencia de nuevas úlceras(solo en pacientes con esclerodermia) 6. Puntuación de la piel (solo en pacientes con esclerodermia)
    E.5.1.1Timepoint(s) of evaluation of this end point
    As soon as the last subject has completed the last visit and all data have been locked, the results will be analysed and described in a Clinical Study Report.
    Una vez el último paciente haya completado la última visita y todos los datos hayan sido cerrados, los resultados serán analizados y descritos en el Informe Final de Resultados.
    E.5.2Secondary end point(s)
    Change from baseline* to V5 and from V1 to V5 for the following parameters:
    1. Pulmonary vascular resistance (PVR), right atrial pressure (RAP), mean pulmonary artery pressure (mPAP), cardiac index (CI) and mixed venous oxygen saturation (SvO2). Further haemodynamic parameters may also be calculated if considered appropriate.

    Change from baseline* to V3 and to V5 and from V1 to V5 for the following parameters:
    2. WHO functional class
    3. 6-minute walk test (6-MWT), including Borg dyspnoea score
    4. Biomarkers (brain natriuretic peptide [BNP] and N-terminal pro brain natriuretic peptide [NT-proBNP])
    5. Echocardiogram parameters:
    • Tricuspid regurgitation, classified as absent, mild, moderate or severe
    • Right ventricular contractility, measured via tricuspid annular plane systolic excursion (TAPSE)
    • Pericardial effusion, classified as absent, traces or present
    • Right atrial area (end-systolic), right ventricular end-diastolic area
    6. Quality of life (SF-36v2)
    Cambio entre el valor de referencia* y la V5 y entre la V1 y la V5 en los siguientes parámetros:
    1. Resistencia vascular pulmonar (RVP), presión auricular derecha (PAD), tensión arterial pulmonar media (PAPm), índice cardíaco (IC) y saturación de oxígeno venoso mixto (SvO2). También podrán calcularse otros parámetros hemodinámicos si se considera adecuado.
    Cambio entre el valor de referencia* y la V3 y entre el valor de referencia* y la V5, y entre la V1 y la V5 en los siguientes parámetros:
    2. Clase funcional de la OMS
    3. Prueba de caminata de 6 minutos (6-MWT, por sus siglas en inglés), i incluída la puntuación de disnea de Borg
    4. Biomarcadores (péptido natriurético cerebral [PNC] y N-terminal pro-péptido natriurético cerebral [NT-proPNC])
    5. Parámetros del ecocardiograma:
    • Regurgitación tricúspide, clasificada como ausente, leve, moderada o grave • Contractilidad ventricular derecha, medida mediante desplazamiento sistólico del plano del anillo tricúspideo (TAPSE, por sus siglas en inglés)Derrame pericárdico, clasificado como ausente, rastros o presente
    • Área auricular derecha (sistólica final), área diastólica final del ventrículo derecho
    6. Calidad de vida (SF-36v2)
    E.5.2.1Timepoint(s) of evaluation of this end point
    As soon as the last subject has completed the last visit and all data have been locked, the results will be analysed and described in a Clinical Study Report.
    Una vez el último paciente haya completado la última visita y todos los datos hayan sido cerrados, los resultados serán analizados y descritos en el Informe Final de Resultados.
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    Ukraine
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    Última visita del último sujeto
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    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: 35
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 35
    F.4.2.2In the whole clinical trial 40
    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)
    Patients will have the opportunity to continue treatment with zamicastat in a compassionate use program.
    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 Decision2019-01-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-09
    P. End of Trial
    P.End of Trial StatusOngoing
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