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    Summary
    EudraCT Number:2012-002988-10
    Sponsor's Protocol Code Number:1392GJK303
    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:2012-09-26
    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 number2012-002988-10
    A.3Full title of the trial
    Randomized, double-blind, placebo-controlled trial to compare the effect, three months of follow-on pulse pressure and vascular function of isosorbide mononitrate extended release, associated with antihypertensive treatment in patients over 65 years refractory isolated systolic hypertension
    ENSAYO CLÍNICO ALEATORIZADO, DOBLE CIEGO, CONTROLADO CON PLACEBO, PARA COMPARAR EL EFECTO, A TRES MESES DE SEGUIMIENTO, SOBRE LA PRESIÓN DE PULSO Y LA FUNCIÓN VASCULAR DE MONONITRATO DE ISOSORBIDE DE ACCIÓN PROLONGADA, ASOCIADO AL TRATAMIENTO ANTIHIPERTENSIVO EN PACIENTES MAYORES DE 65 AÑOS CON HIPERTENSIÓN SISTÓLICA AISLADA REFRACTARIA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized, double-blind, placebo-controlled trial to compare the effect, three months of follow-on pulse pressure and vascular function of isosorbide mononitrate extended release, associated with antihypertensive treatment in patients over 65 years refractory isolated systolic hypertension.
    EL EFECTO, A TRES MESES DE SEGUIMIENTO, SOBRE LA PRESIÓN DE PULSO Y LA FUNCIÓN VASCULAR DE MONONITRATO DE ISOSORBIDE DE ACCIÓN PROLONGADA, ASOCIADO AL TRATAMIENTO ANTIHIPERTENSIVO EN PACIENTES MAYORES DE 65 AÑOS CON HIPERTENSIÓN SISTÓLICA AISLADA REFRACTARIA
    A.3.2Name or abbreviated title of the trial where available
    isosorbide mononitrate extended release, associated with antihypertensive treatment in patients over
    MONONITRATO DE ISOSORBIDE DE ACCIÓN PROLONGADA, ASOCIADO AL TRATAMIENTO ANTIHIPERTENSIVO EN PACIENTE
    A.4.1Sponsor's protocol code number1392GJK303
    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 SponsorFundación para la investigacion Biomedica
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMinisterio de Sanidad , Servicios sociales e Igualdad
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFundacion para la investigacion biomedica
    B.5.2Functional name of contact pointRafael Fernandez
    B.5.3 Address:
    B.5.3.1Street AddressDiego de León 62, 1ªPlanta
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28006
    B.5.3.4CountrySpain
    B.5.4Telephone number5202476
    B.5.5Fax number5202560
    B.5.6E-maileecc.fib.hlpr@salud.madrid.org
    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 CARDIONIL 20 mg cápsulas de liberación prolongada
    D.2.1.1.2Name of the Marketing Authorisation holderALACAN,S.A.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical form Capsule
    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 INN5-mononitrato de isosorbida (D.C.I.), 20 mg
    D.3.9.2Current sponsor codeCARDIONIL 20 mg cápsulas de liberación prolongada
    D.3.9.3Other descriptive nameISOSORBIDE MONONITRATE
    D.3.9.4EV Substance CodeSUB08336MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number40 to 60
    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 placeboCapsule
    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
    Refractory isolated systolic hypertension
    Hipertensión sistólica aislada refractaria
    E.1.1.1Medical condition in easily understood language
    Refractory isolated systolic hypertension
    Hipertensión sistólica aislada refractaria
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    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 compare the effect on clinic pulse pressure of extended release isosorbide mononitrate vs placebo, added to the usual treatment of patients over 65 with refractory ISH, after 3 months of treatment.
    Comparar el efecto a 3 meses sobre la presión de pulso medida en la consulta, de mononitrato de isosorbide de liberación prolongada añadido al tratamiento habitual, en pacientes de 65 años o más con hipertensión sistólica aislada refractaria.
    E.2.2Secondary objectives of the trial
    1.- To quantify the effect on vascular function (estimated by central BP, augmentation index and pulse wave velocity) of extended release isosorbide mononitrate vs placebo, after 3 months of treatment.
    2.- To compare the effect of the addition of extended releasese isosorbide mononitrate on previous parameters, depending on whether HT is truly refractory (mean 24 hour BP >130/80 mmHg) or pseudorefractory (?130/80 mmHg)
    3.- To evaluate the safety profile of the strategy based on the addition of extended release isosorbide mononitrate, by the appearance of adverse effects (with particular attention to headache and orthostatic hypotension).
    4.- To quantify the percentage of patients that reach a clinic sistolyc blood pressure <140mmHg in both treatments groups
    ? Cuantificar el efecto sobre la presión arterial central y la elasticidad vascular, estimada por índice de aumento (IA) y velocidad de onda de pulso (VOP).
    ? Evaluar el perfil de seguridad terapéutico, mediante registro de efectos adversos (frecuencia, tipo, severidad y porcentaje de pacientes en los que son causa abandono).
    ? Cuantificar el porcentaje de pacientes que alcanzan presión arterial sistólica clínica (PAS) <140mmhg.
    ? Cuantificar el porcentaje de pacientes que alcanzan PAS media de 24 horas <130 mmHg en la MAPA.
    ? Cuantificar el efecto sobre la presión de pulso de 24 horas registrada en la MAPA.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ? Patients aged 65 or over of both genders, belong to some primary care or Hypertension?s Unit of Hospital La Princesa, who will be given their written informed consent to participate in the study.
    ? Patients with refractory ISH defined as SBP ?140 mmHg and DBP <90 mmHg, despite treatment with three drugs as maximum doses, one of them diuretic, during at least one month before the start
    ? Good adherence to treatment, defined as a good response to all questions of Morisky-Green?s test.
    ? SBP between 140 y 179 mmHg
    ? Ability to understand study procedures and to comply with them for the entire length of the study.
    ? Life expectancy greater than 1 year
    ? Signing the informed consent
    Se incluirán pacientes de ambos sexos, adscritos a los centros de salud participantes en el estudio o al Hospital Universitario de la Princesa, con los siguientes criterios:
    ? De 65 o más años, con HSA refractaria definida como PAS >=140 mmHg y PAD < 90 mmHg, a pesar de tratamiento con tres fármacos a dosis plenas, uno de ellos diurético, al menos durante el mes previo, en pacientes con buena adherencia la tratamiento.
    ? PAS entre 140 y 179 mmHg
    ? Esperanza de vida mayor a 1 año
    ? Firma del consentimiento informado
    E.4Principal exclusion criteria
    ? Current treatment with nitrites or intolerance to them
    ? Atrial fibrillation
    ? Secondary hypertension
    ? Patients with physical, mental or important communications limitations.
    ? life expectancy less than one year
    ? Malignancy
    ? Congestive heart failure III-IV NYHA
    ? Renal failure IV-V (glomerular filtration measured with MDRD ?30 ml/min)
    ? Hepatic failure
    ? Concomitant treatment with phosphodiesterase 5 during previous month at the beginning of study
    ? Severe anaemia (haemoglobin ?8g/dl)
    ? Simultaneous participation in another clinical trial.
    ? Inability or unwillingness of individual or legal guardian/representative to give written informed consent.
    ? Subjects who don?t give their written consent to participate in the study.
    ? Any other circumstance that, as the researcher criteria, advises against the inclusion to the study
    ? PAS> 179 mmHg.
    ? Tratamiento con nitratos o intolerancia a los mismos.
    ? Contraindicación para el uso de nitratos ( hipersensibilidad, pacientes con glaucoma de ángulo cerrado).
    ? Tratamiento concomitante con inhibidores de la fosfodiesterasa 5 durante el mes previo al inicio del estudio.
    ? Fibrilación auricular.
    ? HTA secundaria.
    ? Pacientes con limitaciones físicas, psíquicas o de comunicación importantes
    ? Insuficiencia cardíaca congestiva estadíos III-IV de la NYHA.
    ? Insuficiencia renal estadios IV-V (filtrado glomerular estimado por MDRD ?30 ml/min).
    ? Insuficiencia hepática o enfermedad oncológica activa.
    ? Anemia severa (definida como hemoglobina ?8g/dl).
    E.5 End points
    E.5.1Primary end point(s)
    - Difference between PP final visit and PP baseline visit: mmHg (office)
    El análisis primario de eficacia será la diferencia sobre la presión de pulso (PP) medida en la clínica, del tratamiento con mononitrato de isosorbide de liberación retardada frente a placebo .
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary efficacy assessment will be the difference between PP in the last visit compared to PP in the screening visit, and it will be demonstrated significantly differences compared to placebo.
    Diferencia entre la presión de pulso (PP) en la visita final respecto a la PP en la visita inicial, en mmHg., medida en consulta.
    E.5.2Secondary end point(s)
    - Difference between SBP( Systolic Blood Pressure)baseline visit and SBP final visit: mmHg (office)
    - Difference between DBP(Diastolic Blood Pressure) baseline visit and DBP final visit: mmHg (office)
    - Difference between PP(Pulse Pressure) baseline visit and PP final visit: mmHg (24 hours mean at ABPM,Ambulatory Blood Pressure Monitoring)
    - Difference between SBP baseline visit and SBP final visit: mmHg (24 hours mean at ABPM)
    - Difference between DBP baseline visit and DBP final visit: mmHg (24 hours mean at ABPM)
    - Difference between PWV baseline(Pulse Wave Velocity) visit and PWV final visit
    - Difference between Central SBP baseline visit and central SBP final visit
    - Difference between Central PP baseline visit and central PP final visit
    - Difference between AI baseline visit and AI final visit
    - Percentage of subjects with SBP<140mmHg at office at the study end
    - Percentage of responders subjects: decrease on SBP (baseline-final) >10 mmHg at office
    - Percentage of subjects with adverse effects and type of adverse effect at 6 and 12 weeks after intervention
    - Percentage of subjects that must abandon the study due to adverse effects.
    - Percentage of patients with orthostatic hypotension (a decrease on SBP >20mmHg and/or DBP >10mmHg after one minute of standing) at each one of the visits
    ? PP visita final- PP visita inicial: mmHg (consulta)
    ? PAS visita final- PAS visita inicial: mmHg (consulta)
    ? PAD visita final- PAd visita inicial: mmHg (consulta)
    ? PP visita final- PP visita inicial: mmHg (MAPA)
    ? PAS visita final- PAS visita inicial: mmHg (MAPA)
    ? PAD visita final- PAd visita inicial: mmHg (MAPA)
    ? VOP visita inicial- VOP visita final
    ? PAS central visita inicial- PAS central visita final
    ? IA visita inicial- IA central visita final
    ? % de sujetos con PAS < 140 al final del estudio
    ? % de sujetos respondedores: descenso de PAS > 10 mmHg
    ? % de sujetos con efectos adversos y tipo de efecto adverso.
    ? % de sujetos con hipotensión ortostática
    E.5.2.1Timepoint(s) of evaluation of this end point
    All of secondary objectives will be measured as the difference between the last visit compared to the inclusion visit.
    Todos los objetivos secundarios se medirán como la diferencia de las variables entre la última visita y la visita de inclusión del estudio.
    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 No
    E.6.7Pharmacodynamic No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 trial1
    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 concerned16
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    Date on which the last subject completed the study follow-up visit.
    Fecha en la que el último sujeto completa la visita de seguimiento del estudio, ya que no están previstos análisis intermedios.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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) No
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 154
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state154
    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)
    After the study the patient can continue with active treatment should be considered relevant.
    Una vez finalizado el estudio el paciente podrá continuar con el tratamiento activo en caso de considerarse pertinente.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.3.4Network Country Spain
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-11-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-08-09
    P. End of Trial
    P.End of Trial StatusCompleted
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