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    Summary
    EudraCT Number:2014-001971-30
    Sponsor's Protocol Code Number:CLCZ696B2317
    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:2014-12-09
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-001971-30
    A.3Full title of the trial
    A multicenter study to evaluate safety and tolerability in patients with chronic heart failure and reduced ejection fraction from PARADIGM-HF receiving open label LCZ696
    Ensayo clínico multicéntrico para evaluar la seguridad y la tolerabilidad en pacientes con insuficiencia cardíaca crónica y reducción de la fracción de eyección de PARADIGM-HF que reciben tratamiento abierto con LCZ696
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and tolerability during open-label treatment with LCZ696 in patients with chronic heart failure and reduced ejection fraction
    Seguridad y tolerabilidad durante el tratamiento abierto con LCZ696 en pacientes con insuficiencia cardíaca crónica y reducción de la fracción de eyección
    A.4.1Sponsor's protocol code numberCLCZ696B2317
    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 SponsorNovartis Farmacéutica, S.A.
    B.1.3.4CountrySpain
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica, S.A.
    B.5.2Functional name of contact pointDepartamento Médico de ICRO
    B.5.3 Address:
    B.5.3.1Street AddressGran Via de les corts Catalanes 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number34900353036
    B.5.5Fax number34932479903
    B.5.6E-maileecc.novartis@novartis.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 nameLCZ696 50mg
    D.3.2Product code LCZ696
    D.3.4Pharmaceutical form Film-coated 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 INNsacubitril/valsartan
    D.3.9.3Other descriptive nameLCZ696
    D.3.9.4EV Substance CodeSUB30457
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 nameLCZ696 100mg
    D.3.2Product code LCZ696
    D.3.4Pharmaceutical form Film-coated 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 INNsacubitril/valsartan
    D.3.9.3Other descriptive nameLCZ696
    D.3.9.4EV Substance CodeSUB30457
    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.IMP: 3
    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 nameLCZ696 200mg
    D.3.2Product code LCZ696
    D.3.4Pharmaceutical form Film-coated 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 INNsacubitril/valsartan
    D.3.9.3Other descriptive nameLCZ696
    D.3.9.4EV Substance CodeSUB30457
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Heart failure with reduced ejection fraction
    Insuficiencia cardíaca con fracción de eyección reducisa
    E.1.1.1Medical condition in easily understood language
    Heart failure
    Insuficiencia cardiaca
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10019279
    E.1.2Term Heart failure
    E.1.2System Organ Class 100000004849
    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 continue to evaluate the safety and tolerability of LCZ696 in heart failure patients from PARADIGM-HF receiving open-label investigational drug.
    El objetivo principal de este estudio es continuar evaluando la seguridad y la tolerabilidad de LCZ696 en pacientes con insuficiencia cardíaca del estudio PARADIGM-HF que reciben tratamiento abierto con el fármaco en investigación.
    E.2.2Secondary objectives of the trial
    Not applicable
    No aplica
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent for the extension must be obtained before any assessment is performed.
    2. Patients who have completed PARADIGM-HF (protocol CLCZ696B2314) and are able to be safely enrolled into the open-label trial as judged by the investigator.
    1. Deberá obtenerse el consentimiento informado por escrito para la extensión antes de que se realice ninguna evaluación.
    2. Pacientes que hayan finalizado el estudio PARADIGM-HF y puedan realizar con seguridad la transición al estudio abierto a criterio del investigador.
    E.4Principal exclusion criteria
    1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is
    longer
    2. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to LCZ696
    3. Known history of angioedema
    4. Requirement of simultaneous treatment with both ACEIs and ARBs 5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy)
    6. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 (screening)
    7. Estimated GFR < 30 mL/min/1.73m2 as measured by the simplified MDRD formula at Visit 1 (screening)
    8. Presence of bilateral renal artery stenosis
    9. Serum potassium > 5.2mmol/L at Visit 1 (screening)
    10. Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 3 x ULN at Visit 1, history of hepatic encephalopathy, history of esophageal varices, or history of portacaval shunt
    11. Pregnant or nursing (lactating) women
    12. Women of childbearing potential
    13. Any condition, not identified in the protocol, that in the opinion of the investigator is likely to prevent the patient from safely tolerating LCZ696 or complying with the requirements of the study.
    1. Uso de otros medicamentos en investigación en el momento de la inclusión, o en el plazo de 30 días o 5 semividas previos al reclutamiento, lo que sea más largo.
    2. Antecedentes de hipersensibilidad o alergia a algún fármaco del estudio, fármacos de grupos químicos similares, IECA, ARA o inhibidores de la EPN así como contraindicaciones presuntas o conocidas a LCZ696.
    3. Antecedentes conocidos de angioedema.
    4. Necesidad de tratamiento simultáneo con IECA y ARA.
    5. IC aguda descompensada actual (exacerbación de una IC crónica manifestada por signos y síntomas que puedan requerir tratamiento intravenoso).
    6. Hipotensión sintomática y/o PAS < 100 mmHg en la visita 1 (selección).
    7. FG estimada < 30 ml/min/1,73 m2 calculada mediante la fórmula MDRD simplificada en la visita 1 (selección)
    8. Presencia de estenosis de la arteria renal bilateral
    9. Potasio sérico > 5,2 mmol/l en la visita 1 (selección)
    10. Signos de hepatopatía determinada por una de las siguientes circunstancias: Valores de AST o ALT > 3 x LSN en la visita 1, antecedentes de encefalopatía hepática, antecedentes de varices esofágicas o antecedentes de derivación portocava.
    11. Mujeres embarazadas o en lactación, definido el embarazo como el estado de la mujer desde la concepción hasta el final de la gestación, confirmado por un resultado positivo en el análisis de HCG (> 5 mUI/ml).
    12. Mujeres en edad fértil, definidas como las que tengan capacidad fisiológica de quedarse embarazadas
    13. Cualquier trastorno que, en opinión del investigador, pueda impedir que el paciente tolere de forma segura LCZ696 o cumplir los requisitos del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary assessments for safety are the reporting of angioedema, AEs that are suspected to be related to LCZ696, AEs leading to study drug discontinuation and serious adverse events (SAE) including death. The assessment of safety will be based primarily on the frequency of adverse events of special interest, sitting systolic and diastolic blood pressure, heart rate, and serious adverse events suspected by the investigators to be related to LCZ696 for the Safety set.
    La evaluación principal de la seguridad es la notificación de angioedema, AA que se sospeche que están relacionados con LCZ696, AA que provoquen la suspensión del fármaco del estudio y los acontecimientos adversos graves (AAG), incluida la muerte.
    La evaluación de la seguridad se basará fundamentalmente en la frecuencia de los acontecimientos adversos de interés especial, presión arterial sistólica y diastólica en sedestación, frecuencia cardíaca y acontecimientos adversos graves que los investigadores sospechen que están relacionados con LCZ696 en el grupo de seguridad.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Total follow up time (up to 30 months)
    Tiempo de seguimiento total (hasta 30 meses)
    E.5.2Secondary end point(s)
    Not applicable
    No aplica
    E.5.2.1Timepoint(s) of evaluation of this end point
    Not applicable
    No aplica
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Safety and tolerability of LCZ696 in patients with chronic heart failure
    Seguridad y tolerabilidad del LCZ696 en pacientes con insuficiencia cardíaca crónica
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 concerned17
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA429
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Belgium
    Brazil
    Bulgaria
    Canada
    Chile
    China
    Colombia
    Czech Republic
    Denmark
    Dominican Republic
    Ecuador
    Estonia
    Finland
    France
    Germany
    Guatemala
    Hong Kong
    Hungary
    Iceland
    India
    Israel
    Italy
    Korea, Republic of
    Latvia
    Lithuania
    Malaysia
    Mexico
    Netherlands
    Panama
    Peru
    Philippines
    Poland
    Romania
    Russian Federation
    Singapore
    Slovakia
    South Africa
    Spain
    Sweden
    Taiwan
    Thailand
    Turkey
    United Kingdom
    United States
    Venezuela, Bolivarian Republic of
    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
    Expected LVLS: 2017-03-31
    LVLS estimado; 31-03-2017
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 2400
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2600
    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 state156
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2123
    F.4.2.2In the whole clinical trial 5000
    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)
    Investigator must provide follow-up medical care for all subjects who are
    prematurely withdrawn from the study, or must refer them for appropriate ongoing
    care
    Investigador debe proporcionar atención médica de seguimiento para todos los
    sujetos que están prematuramente retirados del estudio, o debe remitirlos para
    atención continua apropiada
    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 Decision2015-02-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-12-27
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