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    Summary
    EudraCT Number:2016-003789-21
    Sponsor's Protocol Code Number:MULTBENZ
    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:2016-11-17
    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 number2016-003789-21
    A.3Full title of the trial
    Phase II trial for assessing different benznidazol regimens in the treatment of Chagas disease in adult patients on chronic phase . BERINECE project
    Ensayo clínico fase II para la evaluación de diferentes regímenes de benznidazol como tratamiento de la enfermedad de Chagas en fase crónica en pacientes adultos. Proyecto BERENICE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase II trial for assessing different benznidazol regimens in the treatment of Chagas disease in adult patients on chronic phase . BERINECE project
    Ensayo clínico fase II para la evaluación de diferentes regímenes de benznidazol como tratamiento de la enfermedad de Chagas en fase crónica en pacientes adultos. Proyecto BERENICE
    A.3.2Name or abbreviated title of the trial where available
    MULTBENZ
    MULTBENZ
    A.4.1Sponsor's protocol code numberMULTBENZ
    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 Hospital Universitari Vall d'Hebron - Institut de Recerca
    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 supportEuropean Comission
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFundación Hospital Universitari Vall d'Hebron - Institut de Recerca
    B.5.2Functional name of contact pointPROSICS
    B.5.3 Address:
    B.5.3.1Street AddressPasseig de la Vall d'Hebron, 119-129
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08035
    B.5.3.4CountrySpain
    B.5.4Telephone number34932746080
    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 nameBenznidazol
    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 INNBENZNIDAZOLE
    D.3.9.1CAS number 22994-85-0
    D.3.9.4EV Substance CodeSUB05753MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number150 to 400
    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
    Chagas Disease on chronic phase
    Enfermedad de Chagas en fase crónica
    E.1.1.1Medical condition in easily understood language
    Chagas Disease on chronic phase
    Enfermedad de Chagas en fase crónica
    E.1.1.2Therapeutic area Diseases [C] - Parasitic Diseases [C03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10008384
    E.1.2Term Chagas' disease
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the effectiveness of different regimens of benznidazole by the proportion of patients with sustained suppression of the parasitic load measured by PCR in peripheral blood during the first 12 months of follow up after the start of treatment in patients older than 18 years with Chagas disease in chronic phase in both its indeterminate or organic form (digestive or heart ) .
    Evaluar la eficacia de diferentes regímenes de benznidazol mediante la proporción de pacientes que presentan una supresión mantenida de la carga parasitaria medida con PCR en sangre periférica durante los primeros 12 meses de seguimiento tras el inicio del tratamiento, en pacientes igual o mayores de 18 años con enfermedad de Chagas en fase crónica tanto en su forma indeterminada como en las orgánicas (digestiva o cardiaca).
    E.2.2Secondary objectives of the trial
    - Assess for different regimes, the parasitic kinetic at week 1,2,4 and 8 of treatment and 4,6,8 and 12 months after starting treatment in patients over 18 with chronic phase Chagas both its indeterminate form and organic ( gastrointestinal or cardiac )
    -Evaluate for different regimes, the serologic response in chronic phase indeterminate form both in symptomatic and by trend curves OD by ELISA methods
    -Assess tolerability and safety of different regimens of benznidazole for Chagas disease in chronic phase, in form with or without apparent pathology ( digestive or heart )
    - Correlate Benznidazol blood levels in the equilibrium phase with the therapeutic response and adverse effects.
    - Correlate the presence of HLA B3505 with serious side effects
    - Correlate different DTUs parasites and geographical origins with therapeutic response
    •Evaluar para los diferentes regímenes la cinética parasitaria a la semana 1,2,4 y 8 de tratamiento y a los 4,6,8 y 12 meses del inicio del tratamiento en pacientes mayores de 18 años con Chagas en fase crónica tanto en su forma indeterminada como en las orgánicas (digestiva o cardiaca)
    •Evaluar en los diferentes regímenes la respuesta serológica en fase crónica tanto en su forma indeterminada como en las sintomáticas, mediante curvas de tendencia de DO de los métodos de ELISA
    •Valorar tolerabilidad y seguridad de los diferentes regímenes de benznidazol para la enfermedad de Chagas en fase crónica, en su forma con o sin patología aparente (digestiva o cardiaca)
    •Correlacionar los niveles de benznidazol en sangre en la fase de equilibrio, con la respuesta terapéutica y los efectos adversos.
    •Correlacionar la presencia del HLA B3505 con efectos secundarios graves
    •Correlacionar los diferentes DTUs de los parásitos así como los orígenes geográficos con la respuesta terapéutica.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients ≥ 18 years old
    - Patients diagnosed of Chagas disease through 2 positive serologic tests, using different antigens.
    - Detectable DNA of T.Cruzi in peripheral blood through PCR.
    - Written Informed Consent
    - Weight ≥ 50 kg to ≤80 kg
    - Patients capable to fulfill with the protocol visits and procedures and have a permanent address
    - Patients must be residents of Free Areas transmission vector (Triatoma infestans). (Defined by local health programs or under the definition of PAHO / WHO
    - Childbearing Woman with a negative pregnancy test in serum or urine at baseline. During the treatment phase, breastfeeding is not allow and a barrier contraceptive method has to be used.
    - Adultos iguales o mayores de 18 años.
    - Haber sido diagnosticado de enfermedad de Chagas mediante la positividad 2 test serológicos, que utilicen diferentes antígenos.
    - Tener una DNA de T. cruzi detectable en sangre periférica mediante una interpretación cualitativa de la técnica de PCR.
    - Consentimiento informado escrito.
    - Peso≥ 50 kg a ≤80 kg.
    - Capacidad para cumplir con todas las pruebas y visitas de protocolo especificado y tener una dirección permanente.
    - Los pacientes deben ser residentes de áreas libres de transmisión del vector (Triatoma infestans). (definida por los programas de salud local o en virtud de la definición de la OPS/OMS).
    - Las mujeres en edad fértil deben tener una prueba de embarazo en orina o en suero negativa en la visita basal. No se debe dar lactancia materna, y debe utilizar un método de barrera de contracepción durante la duración de la fase de tratamiento
    E.4Principal exclusion criteria
    - Patients treated previously with benznidazol o nifurtimox (complete or incomplete)
    - Inability to do the Follow Up at the stipulated dates
    - Acute or chronic health problems, that according to PI opinion can interfere in the efficacy and/or safety drug evaluation (exemple: acute infections, HIV infection, hepatic disease with liver function affected and renal disease that needs supportive treatment)
    - Precedent of alcohol abuse
    - Patients with Known hypersensibility to nitroimidazols, for example metronidazol
    - Any concomitant use or a history of use of allopurinol, antimicrobial or anti-parasitic agents or antifungal
    - Laboratory parameters out of range o clinically relevant according to investigator criteria:
    o Leukocytes must be within the normal range, with an acceptable margin of +/- 5%
    o Platelets must be within the normal range up to 550,000 / mm3 or 550x109 / L
    o Total bilirubin must be within the normal range

    o Transaminases (ALT and AST) should be within the normal range, with an acceptable margin of 25% above the upper limit of normal (ULN) <1.25 x ULN.
    o Creatinine should be within the normal range, with an acceptable margin of 10% above the ULN, <1.10 x ULN.
    o Alkaline phosphatase must be within the normal range until CTCAE Grade 1 (<2.5 x ULN)
    o GGT should be within the normal range up to 2x ULN.
    o Fasting glucose should be within the normal range
    - Haber recibido tratamiento previo con benznidazol o nifurtimox (ya sea de forma completa o incompleta).
    - Imposibilidad para poder hacer seguimiento en las fechas estipuladas.
    - Problemas de salud agudos o crónicos que, en opinión del IP, pueden interferir con la evaluación de la eficacia y / o seguridad del fármaco (por ejemplo, infecciones agudas, infección por VIH, hepatopatías con compromiso de la función hepática y enfermedad renal que requiera tratamiento de soporte).
    - Antecedentes de abuso de alcohol.
    - Los pacientes con alguna contraindicación (hipersensibilidad conocida) a cualquier nitroimidazoles, por ejemplo, metronidazol.
    - Cualquier uso concomitante o antecedentes de uso de alopurinol, antimicrobianos, o agentes anti-parasitarios o antifúngicos.
    - Tener parámetros de laboratorio fuera del rango de la normalidad o que se consideren clínicamente relevantes por parte del médico responsable del paciente:
    o Los leucocitos deben estar dentro del rango normal, con un margen aceptable de +/- 5%.
    o Las plaquetas deben estar dentro del rango normal hasta 550.000 / mm3 o 550x109/L
    o La bilirrubina total debe estar dentro del rango normal
    o Las transaminasas (ALT y AST) debe estar dentro del rango normal, con un margen aceptable de 25% por encima del límite superior de la normalidad (LSN) <1,25 x LSN.
    o La creatinina debe estar dentro del rango normal, con un margen aceptable de 10% por encima del LSN, <1.10 x LSN.
    o La fosfatasa alcalina debe estar dentro del rango normal hasta el Grado 1 CTCAE (< 2,5 x LSN)
    o La GGT debe estar dentro del rango normal hasta 2x LSN.
    o La glucosa en ayunas debe estar dentro del rango normal
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy:
    Parasitological response determined by the presence of parasite DNA in peripheral blood measured by PCR and interpreted qualitatively during the treatment and follow-up. Treatment times and are defined by monitoring the different treatment arms.
    Safety:
    - Incidence and severity of the side effects
    - Treatment interruption
    Eficacia:
    Respuesta parasitológica determinada mediante la determinación de la presencia de ADN parasitario en sangre periférica medida mediante PCR e interpretada de manera cualitativa durante la fase de tratamiento y de seguimiento. Los tiempos de tratamiento y de seguimiento vienen definidos por las diferentes ramas de tratamiento
    Seguridad:
    • Incidencia y gravedad de los efectos adversos
    • Interrupciones de tratamiento
    E.5.1.1Timepoint(s) of evaluation of this end point
    15 or 60 days depending on the treatment arm
    15 o 60 días dependiendo de la rama de tratamiento
    E.5.2Secondary end point(s)
    Negativization maintained during the treatment phase and the first 12 months of follow up.
    • Proportion of patients with positive PCR in each of the points of analysis.
    • Changes in the parasite load in the different points of analysis measured by detecting parasite DNA in peripheral blood by quantitative PCR
    • Evolution of the serological response comparing baseline results with the end of follow-up results.
    • Range of biomarker levels decreased at 6 and 12 months follow-up on the screening visit
    • Proportion of patients achieving marker levels decrease below the threshold of positivity (previously defined).
    • Negativización mantenida durante la fase de tratamiento y a los primeros 12 meses de seguimiento.
    • Proporción de pacientes con PCR positiva en cada uno de los puntos de análisis.
    • Cambios en la carga parasitaria en los diferentes puntos de análisis medidas mediante la detección de ADN parasitario en sangre periférica mediante una PCR cuantitativa
    • Evolución de la respuesta serológica comparando los valores iniciales con los del final de seguimiento.
    • Grado de disminución de niveles de biomarcadores a los 6 y 12 meses de seguimiento respecto a la visita de selección
    • Proporción de pacientes que consiguen disminuir los niveles de marcadores por debajo el umbral de positividad (definido previamente).
    E.5.2.1Timepoint(s) of evaluation of this end point
    - During treatment phase and 12 months after treatment
    - Different time point.
    - Different time point
    - At the end of follow up
    - 6 and 12 months follow-up period
    - Different time point
    - Durante la fase de tratamiento y 12 meses después del tratamiento
    - En diferentes puntos
    - En diferentes puntos
    - Al finalizar el periodo de seguimiento
    - a los 6 y 12 meses del periodo de seguimiento
    - En diferentes puntos
    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 Yes
    E.6.6Pharmacokinetic Yes
    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 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other 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 Yes
    E.8.2.3.1Comparator description
    Diferentes dosis del producto en investigación
    Different doses of IMP
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 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
    Brazil
    Colombia
    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
    LVLS
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months16
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months16
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 240
    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)
    Accoding to Standard-of-Care
    De acuerdo a la práctica clínica habitual
    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 Decision2017-01-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-16
    P. End of Trial
    P.End of Trial StatusOngoing
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