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    Summary
    EudraCT Number:2016-004311-12
    Sponsor's Protocol Code Number:RUTIVAC-1
    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:2016-12-15
    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 number2016-004311-12
    A.3Full title of the trial
    A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II TRIAL TO EVALUATE THE IMMUNOMODULATORY EFFECT OF RUTI® IN INDIVIDUALS WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC) TREATED WITH INTRAVESICAL BACILLUS CALMETTE-GUÉRIN (BCG)
    ENSAYO CLÍNICO ALEATORIZADO,DOBLE CIEGO, CONTROLADO CON PLACEBO FASE II PARA EVALUAR EL EFECTO INMUNOMODULADOR DE RUTI® EN INDIVIDUOS CON CARCINOMA SUPERFICIAL DE VEJIGA DE ALTO GRADO TRATADOS CON BACILLUS CALMETTE-GUÉRIN (BCG) INTRAVESICAL.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical response to intravesical BCG therapy of superficial bladder cancer by prior administration of RUTI®
    Respuesta clínica al tratamiento de carcinoma superficial de vejiga con BCG intravesical después de la administración de RUTI®
    A.4.1Sponsor's protocol code numberRUTIVAC-1
    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 SponsorARCHIVEL FARMA, S.L.
    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 supportARCHIVEL FARMA, S.L.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationARCHIVEL FARMA, S.L.
    B.5.2Functional name of contact pointCEO ARCHIVEL FARMA, S.L.
    B.5.3 Address:
    B.5.3.1Street AddressFogars de Tordera, 61
    B.5.3.2Town/ cityBadalona
    B.5.3.3Post code08916
    B.5.3.4CountrySpain
    B.5.4Telephone number+3493 497 24 56
    B.5.5Fax number+3493 497 24 57
    B.5.6E-mailorue@archivelfarma.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 nameRUTI
    D.3.4Pharmaceutical form Suspension 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 INNRUTI
    D.3.9.2Current sponsor codeRUTI
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number66.7
    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) Yes
    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 placeboInjection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    High-Risk Non-Muscle-Invasive Bladder Cancer
    Carcinoma superficial de vejiga de alto grado
    E.1.1.1Medical condition in easily understood language
    Bladder cancer
    Cáncer de vejiga
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10005003
    E.1.2Term Bladder cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the systemic and mucosal immunological response of RUTI® administration prior to intravesical BCG therapy in individuals with high-risk NMIBC.
    Immunological changes will be evaluated after completion of intravesical BCG therapy.
    Evaluar la respuesta inmunológica sistémica y en mucosa tras la administración de RUTI® y previa a la terapia intravesical con BCG en individuos con CSV de alto grado.
    Los cambios inmunológicos serán evaluados después de la finalización de tratamiento intravesical con BCG.
    E.2.2Secondary objectives of the trial
    • To determine the efficacy of RUTI® administration prior to intravesical BCG therapy in individuals with high-risk NMIBC at 12, 24 and 36 months after randomization in terms of:
    - Recurrence rate
    - Disease worsening
    - Overall survival
    • To analyze the correlation of rates of recurrence with systemic and local immunological changes.
    • To evaluate the safety and tolerability of RUTI® in individuals with high-risk NMIBC.
    • Determinar la eficacia de la administración de RUTI® antes del tratamiento intravesical con BCG en individuos con CSV de alto grado a los 12, 24 y 36 meses después de la aleatorización en términos de:
    - Tasa de recurrencia
    - Empeoramiento de la enfermedad
    - Supervivencia global
    • Analizar la correlación entre la tasa de recurrencia y los cambios inmunológicos sistémicos y en la mucosa.
    • Evaluar la seguridad y tolerabilidad de RUTI® en individuos con CSV de alto grado.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written ICF for participation in the study.
    2. Age ≥18 years.
    3. General health status according to WHO ≤ 2.
    4. Have primary histologically confirmed T1 and/or high grade tumors and/or CIS.
    5. All visible papillary tumors must be completely resected.
    6. Early postoperative (within 24 hours of TURBT) single dose chemotherapy is allowed.
    7. BCG therapy indication.
    8. Never treated with BCG immunotherapy
    9. Willing to comply with study visits and procedures as per protocol
    10. Use of reliable contraception (see section 8.6) from the screening visit to 30 days after the last RUTI® or placebo injection.
    1. Firma del consentimiento informado para la participación en el estudio.
    2. Edad igual o superior a 18 años.
    3. Estado general de salud igual o superior a 2, de acuerdo con la OMS.
    4. Tener T1 primario confirmado histológicamente y/o tumores de alto grado y / o CIS.
    5. Todos los tumores papilares visibles deben estar completamente reseccionados.
    6. Se permite una dosis única temprana (dentro de las 24h después de la RTU) de quimioterapia.
    7. Indicación de tratamiento con BCG.
    8. Nunca tratado con inmunoterapia con BCG.
    9. Voluntad de seguir las visitas y procedimientos del estudio marcadas por el protocolo.
    10. Uso de un sistema anticonceptivo (ver sección 8.6 del protocolo) desde la visita de selección hasta 30 días después de la última administración de RUTI® o placebo.
    E.4Principal exclusion criteria
    1. Life expectancy <5 years.
    2. Have a severe concomitant disease that might limit compliance or completion of the protocol.
    3. Have any other malignancy that might impact 3-year survival or might be potentially confused with NMIBC.
    4. Have other neoplasms.
    5. Have congenital or acquired immune deficiencies.
    6. Be receiving cytotoxic drugs, systemic corticosteroids or antiplatelet or anticoagulant therapy within 8 weeks of receiving the first administration of BCG.
    7. Have received radiation therapy for their bladder cancer within 4 months prior to study entry.
    8. Have active infections (including urinary tract infections) defined as viral, bacterial, or fungal infections requiring therapy, HIV-positive status, concurrent febrile illness, gross hematuria or other factor that could influence tolerability to intravesical BCG therapy.
    9. Have biopsy, TURBT, or traumatic catheterization within 14 days of start of intravesical BCG treatment.
    10. Have previous clinical history of tuberculosis.
    11. Active pregnancy or breastfeeding.
    1. Esperanza de vida inferior a 5 años.
    2. Tener una enfermedad concomitante grave que pueda limitar el cumplimiento o finalización del protocolo.
    3. Tener cualquier neoplasia maligna que pudiera afectar la supervivencia a los 3 años o podría potencialmente confundirse con el carcinoma superficial de vejiga de alto grado.
    4. Tener otras neoplasias.
    5. Tener deficiencias congénitas o inmunes adquiridas.
    6. Estar tomando fármacos citotóxicos, corticoesteroides sistémicos o tratamiento antiplaquetario o anticoagulante dentro de las 8 semanas antes de la primera administración de BCG.
    7. Haber recibido tratamiento con radiación para el cáncer de vejiga dentro de los 4 meses antes de la inclusión en el estudio.
    8. Tener infecciones activas (incluyendo infecciones del tracto urinario) definidas como virales, bacteriales o fúngicas que requiera tratamiento, ser VIH-positivo, enfermedad febril concurrente, hematuria macroscópica o otros factores que puedan incluir en la tolerabilidad del tratamiento intravesical con BCG.
    9. Haberse hecho biopsias, RTU o cateterización traumática en los 14 días previos al inicio del tratamiento con BCG intravesical.
    10. Historia clínica previa de tuberculosis.
    11. Embarazo o lactancia.
    E.5 End points
    E.5.1Primary end point(s)
    • Changes in the systemic Th1 immune response will be evaluated as:
    o IFN-γ production assessed by ELISPOT after ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with PPD.
    o IFN-γ and IL-2 production assessed by intracellular staining after ex vivo stimulation of PBMCs with PPD.
    o IFN-γ secretion after long-term stimulation of whole blood assessed by ELISA after stimulation with PPD.

    • Changes in the local Th1/Th2 immune response.
    o Th-1 (T-bet+) and Th2 (GATA-3+) cells present in the peritumoral tissue in samples from TURBT and after the induction course (VISIT1).
    o Urine levels of IL-2, IL-8, IL-6, IL-1RA, IL-10, IL-12 (p70), and TRAIL by LUMINEX.
    • Cambios en la respuesta immune sistémica Th1, se evaluarán como:
    o Producción de IFN-γ evaluada por ELISPOT después de la estimulación ex vivo de PBMCs con PPD.
    o Producción de IFN-γ y IL-2 evaluada por tinción intracelular después de la estimulación ex vivo de PBMCs con PPD.
    o Producción de IFN-γ después de esimulación prolongada en sangre total por ELISA después de estimulación con PPD.

    • Cambios en la respuesta immune local Th1/Th2.
    o Celulas Th-1 (T-bet+) i Th2 (GATA-3+) presentes en tejido peritumoral.
    o Niveles de IL-2, IL-8, IL-6, IL-1RA, IL-10, IL-12 (p70) y TRAIL por LUMINEX en orina.
    E.5.1.1Timepoint(s) of evaluation of this end point
    • Changes in the systemic Th1 immune response will assessed in RUTI1, RUTI2, BCG1, BCG6 and BCG12 samples. Depending on the results further assessment will be performed in BCG9 and BCG15 samples.

    • Changes in the local Th1/Th2 immune response:
    o Th-1 (T-bet+) and Th2 (GATA-3+) cells present in the peritumoral tissue in samples from TURBT and after the induction course (VISIT1).
    o Urine parameters will be assessed in samples from RUTI1, RUTI2, BCG1, BCG6, VISIT1 and BCG12. Depending on the results, further assessment will be performed in BCG9 and BCG15 samples.
    • Los cambios en la respuesta immune sistémica Th1 se evaluarán en muestras de las visitas RUTI1, RUTI2, BCG1, BCG6 y BCG12. Dependiendo de los resultados, se relizarán análisis posteriores en muestras de las visitas BCG9 y BCG15.

    • Los cambios en la respuesta inmune local Th1/Th2 se evaluarán:
    o Las células Th-1 (T-bet+) yTh2 (GATA-3+) presentes en el tejuido peritumoral en muestras de la RTU y de después del curso de inducción (VISIT1).
    o Los parámetros de orina se evaluarán en muestras de las visitas RUTI1, RUTI2, BCG1, BCG6 y BCG12. Dependiendo de los resultados, se relizarán análisis posteriores en muestras de las visitas BCG9 y BCG15.
    E.5.2Secondary end point(s)
    • Recurrence date.
    • Disease worsening.
    • Death date.
    • Safety of RUTI® .:
    o Proportion of patients who develop a Grade 3 or 4 local reactions.
    o Proportion of patients who develop a Grade 3 or 4 systemic reactions.
    o A descriptive summary of any local and systemic events, including severity, durability and relationship to study product.
    • Fecha de recurrencia.
    • Empeoramiento de la enfermedad.
    • Fecha de la muerte
    • Seguridad de RUTI:
    o Proporción de pacientes que desarrollan reacciones de grado 3 o 4.
    o Proporción de pacientes que desarrollan reacciones sistémicas de grado 3 o 4.
    o Resumen descriptivo de todos los acontecimientos locales y sistémicos, incluyendo la intensidad, duración y la relación con el producot en estudio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    From baseline to end-of-study.
    Desde la visita basal hasta el final 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 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
    Immunological response
    Respuesta inmunológica.
    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 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 trial2
    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 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
    End of trial will be 3 years after last transurethral resection of bladder tumor.
    End of Interventional Phase will be last visit BCG15 of last subject.
    El fin del estudio será 3 años después de la última reseción transuretral.
    El fin de la fase de intervención será la última visita BCG15 del último sujeto.
    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 months
    E.8.9.1In the Member State concerned days
    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: 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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Old patients with legal incapacitation
    Pacientes ancianos incapacitados legalmente.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    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)
    Usual clinical practice.
    Practica 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 Decision2017-02-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-10
    P. End of Trial
    P.End of Trial StatusOngoing
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