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    Summary
    EudraCT Number:2020-002518-42
    Sponsor's Protocol Code Number:FIBRO-COVID
    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:2020-10-28
    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 number2020-002518-42
    A.3Full title of the trial
    A RANDOMIZED PHASE-II CLINICAL TRIAL TO EVALUATE THE EFFECT OF PIRFENIDONE COMPARED WITH PLACEBO IN PULMONARY FIBROSIS POST-COVID 19:
    ENSAYO CLÍNICO RANDOMIZADO FASE-II, PARA EVALUAR EL EFECTO DE PIRFENIDONA COMPARADO CON PLACEBO EN LA FIBROSIS PULMONAR POST-COVID19
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    EVALUATING THE EFFECT OF PIRFENIDONE COMPARED WITH PLACEBO IN PULMONARY FIBROSIS POST-COVID 19
    ENSAYO CLÍNICO PARA EVALUAR EL EFECTO DE PIRFENIDONA COMPARADO CON PLACEBO EN LA FIBROSIS PULMONAR POST-COVID19
    A.4.1Sponsor's protocol code numberFIBRO-COVID
    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 SponsorIDIBELL
    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 supportRoche
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDynamic Science SL
    B.5.2Functional name of contact pointClinical Trial Department
    B.5.3 Address:
    B.5.3.1Street AddressAzcona 31
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28028
    B.5.3.4CountrySpain
    B.5.4Telephone number0034914561105
    B.5.5Fax number0034914561126
    B.5.6E-mailensayosclinicos@dynasolutions.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 Yes
    D.2.1.1.1Trade name Esbriet 267 mg
    D.2.1.1.2Name of the Marketing Authorisation holderF. Hoffmann-La Roche AG
    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.3.1Product nameEsbriet
    D.3.4Pharmaceutical form Capsule, hard
    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 INNPIRFENIDONE
    D.3.9.1CAS number 53179-13-8
    D.3.9.4EV Substance CodeSUB09907MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1602 to 2403
    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 placeboTablet
    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
    Pulmonary fibrosis induced by SARS-COV2 virus (post-COVID19 pulmonary sequelae)
    Fibrosis pulmonar inducida por infección vírica SARS-COV2 (secuelas pulmonares post-COVID19)
    E.1.1.1Medical condition in easily understood language
    Pulmonary fibrosis (COVID19)
    Fibrosis pulmonar (COVID19)
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10037383
    E.1.2Term Pulmonary fibrosis
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level HLT
    E.1.2Classification code 10084510
    E.1.2Term Coronavirus infections
    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
    To evaluate the effect of pirfenidone and the safety profile in subjects who have presented severe SARS-COV2 pneumonia, after recovery from associated ARDS, and who present clinical-radiological signs of pulmonary fibrosis. The effect of pirfenidone will be measured after 6 months of treatment by:
    ● % change in FVC
    ● Radiological change in % of pulmonary fibrosis (Chest HRCT)
    Evaluar el efecto de pirfenidona y el perfil de seguridad en sujetos que han presentado neumonía SARS-COV2 severa, tras recuperarse del SDRA asociado, que presentan signos clínico-radiológicos de fibrosis pulmonar, comparado con placebo. El efecto positivo de pirfenidona se medirá tras 6 meses de tratamiento mediante:
    - % de cambio en CVF
    - Cambio radiológico en el % de fibrosis pulmonar (TACAR Tórax)
    E.2.2Secondary objectives of the trial
    ● To assess the clinical-radiological characteristics of patients in both arms (pirfenidone versus placebo).
    ● To study whether there is a clinically significant improvement in patients treated with pirfenidone
    ● % of cases with progression of pulmonary fibrosis
    ● Death or lung transplant (transplant free-survival time)
    ● To investigate whether pirfenidone improves exercise capacity
    ● Improvement in quality of life
    ● Hospitalizations or urgent visits (Emergency or Day-care Hospital) of respiratory cause (infection, exacerbation, post-COVID19 respiratory complications)
    ● To analyse the safety profile of pirfenidone in patients with fibrotic lung lesions following recovery from severe COVID19 pneumonia with associated ARDS. Frequency and severity of events, changes in vital signs and blood tests (mainly liver and kidney profile).
    • Evaluar las características clínico-radiológicas de los pacientes en ambas ramas (pirfenidona versus placebo).
    • Mejoría clínicamente significativa en pacientes tratados con pirfenidona (incremento de > 10% en la CVF y/o de > 15% de la DLCO).
    • Si pirfenidona mejora la capacidad de ejercicio (> 50 metros de diferencia recorridos) y reduce la caída de saturación de oxígeno con el mismo
    • Mejora de la calidad de vida (diferencia total en el score K-BILD igual o mayor de 5)
    • Analizar el perfil de seguridad de pirfenidone en pacientes con lesiones pulmonares fibróticas tras la recuperación de una neumonia COVID19 severa con SDRA asociado. Frecuencia y severidad de los eventos, cambios en signos vitales y en los valores analíticos sanguíneos (perfil hepático y renal principalmente).
    • Hospitalizaciones (> 24h de ingreso) o visitas urgentes (Urgencias o Hospital de Día) de causa respiratoria (infección, agudización, complicaciones post-COVID19)
    • Muerte o trasplante pulmonar.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ● Age > 18 years
    ● Signed Informed Consent Form
    ● Ability to comply with the study protocol in the opinion of the Investigator
    ● Confirmation of SARS-COV2 infection in previous weeks (with negative PCR at study entry), which induced severe pneumonia and ARDS, with subsequent torpid recovery and/or incipient clinical-radiological signs of pulmonary fibrosis.
    ● HRCT with fibrotic radiological changes of at least 5% after recovery from the acute process (HRCT chest during the screening period, performed minimum after 1 month of the acute phase and maximum 90 days after hospital discharge)
    ● Be able to understand the information given and sign the informed consent
    ● For women or men of childbearing age who are not sterile, a commitment to use non-hormonal contraception during the 24-week treatment period will be required.
    • Edad > 18 años
    • Consentimiento informado firmado
    • Confirmación de infección SARS-COV2 en las semanas previas (con PCR negativa en la inclusión al estudio), que haya inducido neumonía grave y SDRA, con recuperación tórpida posterior y/o signos incipientes clínico-radiológicos de fibrosis pulmonar
    • Cambios fibróticos radiológicos de al menos el 5% en el TACAR tórax tras la recuperación del proceso agudo (TACAR tórax realizado como mínimo tras 1 mes de la fase aguda y como máximo 90 días tras el alta hospitalaria).
    • Capacidad de cumplir con el protocolo de estudio (en opinión del investigador)
    • Ser capaz de entender la información que se le da y firmar el consentimiento informado
    • Para mujeres o hombres en edad fértil que no sean estériles se requerirá el compromiso de utilizar contraceptivo no-hormonal durante el periodo de tratamiento de 24 semanas.
    E.4Principal exclusion criteria
    ● Use of systemic steroids (oral or intravenous) at doses greater than 15 mg/day one month prior to randomisation.
    ● Severe or moderate myopathy that may associate a decrease of FVC.
    ● Severe or life-limiting chronic disease prior to COVID19 infection, including severe asthma, cancer, clinical dementia, IPF, or uncontrolled ischemic cardiomyopathy.
    ● Treatment with pirfenidone or nintedanib prior to Covid19
    ● Concomitant treatment with significant interactions with pirfenidone (such as fluvoxamine).
    ● Participation in any other investigational trial throughout the study
    ● Active smoking.
    ● Relevant blood alterations in the analysis made during the screening period:
    o Total bilirubin > 2 ULN
    o AST/SGOT or ALT/SGPT > 2.5 ULN
    o Alkaline phosphatase >3.0 ULN
    o Creatinine Clearance <40 mL/min, calculated by the Cockcroft-Gault formula
    ● Pregnancy or lactation
    ● Concomitant treatments that can cause severe digestive problems.
    ● Gastric surgery in the last 3 months or similar procedures that may increase gastric intolerance.
    ● Inability to complete required visits.
    ● Previous intolerance or allergy to pirfenidone or hypersensitivity to any of its excipients.
    ● History of angioedema
    • Utilización de corticoides sistémicos (oral o endovenoso) a dosis mayor de 15 mg/día un mes antes de la randomización.
    • Miopatía moderada-severa que pueda asociar descenso de la CVF
    • Enfermedades crónicas severas o limitantes de vida previo a la infección por COVID, incluyendo asma grave, FPI, cáncer, demencia clínica, o cardiomiopatía isquémica no controlada.
    • Tratamiento con pirfenidona o nintedanib antes del COVID19
    • Tratamiento concomitante que presente interacciones importantes con pirfenidona (como fluvoxamina).
    • Participación en otro ensayo clínico durante el periodo de estudio.
    • Tabaquismo activo.
    • Alteraciones sanguíneas relevantes en la analítica hecha durante periodo de screening:
    o Bilirrubina total > 2 ULN
    o AST/SGOT or ALT/SGPT > 2.5 ULN
    o Fosfatasa alcalina >3.0 ULN
    o Clearance de creatinina <40 mL/min, calculada mediante la fórmula Cockcroft-Gault
    • Embarazo o lactancia
    • Tratamientos concomitantes que puedan causar problemas digestivos severos.
    • Cirugía gástrica en los últimos 3 meses o procedimientos similares que puedan incrementar la intolerancia gástrica.
    • Incapacidad para cumplimentar las visitas requeridas.
    • Intolerancia o alergia previa a pirfenidona o hipersensibilidad a alguno de sus excipientes.
    • Historia de angioedema
    E.5 End points
    E.5.1Primary end point(s)
    Clinical success rate defined by the percentage of patients who improve functionally (≥10% change in FVC) and radiologically (% of fibrotic signs in chest HRCT)
    Tasa de éxito clínico definido según el porcentaje de pacientes que mejoran funcionalmente (% de cambio en CVF) y radiológicamente (% de signos fibróticos en el TACAR tórax).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The assessment of the primary point is at 6 months.
    La valoración de la variable primaria es a los 6 meses.
    E.5.2Secondary end point(s)
    o Semi-annual rate of change in % FVC
    o HRCT Chest Fibrotic Score. HRCT scans will be obtained with 1-mm collimation and a 1-mm slice thickness at 10-mm intervals from the lung apices to the bases with the patient in the supine position at full inspiration. Two observers, unaware of the clinical data and lung function of the patients, will evaluate the data independently.
    The fibrotic HRCT findings (reticulation, traction bronchiectasis, honeycombing) will be assessed in three (upper, middle and lower) zones of each lung. The extent of each HRCT finding will be determined by visually estimating the percentage of parenchymal involvement in each zone. The six zone scores will be averaged to determine the total score for each patient. The HRCT fibrosis score will be recorded at the initial diagnosis and after six months in a same manner, and an investigation regarding the chronological changes in these values will be conducted. The manual score of every anonymized HRCT scan will be checked in IDIBELL by using the CALIPER software for automatically calculating fibrotic HRCT score.
    o Incidence of drug-associated adverse events (nature, seriousness, severity, frequency, causality, clinical consequence and time since drug onset) including nausea, diarrhea, abdominal pain, vomiting, headache, hypertransaminasemia
    o discontinuation of treatment.
    o % of cases with progression of pulmonary fibrosis (decrease in FVC ≥ 10% and/or of DLCO ≥ 15% and/or appearance of honeycomb images on HRCT chest when previously there was none).
    o Exercise capacity (improvement in % oxygen saturation at the end of the 6-minute walk test or increase in meters walked greater than 50 meters)
    o Decreased oxygen requirement for physical activity
    o Improvement in quality of life (difference in final K-BILD score greater than 5)
    o Hospitalizations or urgent visits (to the Emergency Room or out-patient Hospital) of a respiratory cause (infection, exacerbation, post-COVID19 complications)
    o Lung transplant or death
    o Tasa de cambio en el % de CVF a los 6 meses del tratamiento
    o Puntuación fibrótica TACAR tórax. Las imágenes del TACAR torax se obtendrán con 1 mm de grosor en intervalos de 10 mm desde los ápex hasta las bases con el paciente en posición supino y máxima inspiración. Dos observadores, sin información clínica ni función respiratoria de los pacientes, evaluaran las imágenes de forma independiente. Los cambios fibróticos (engrosamiento reticular, bronquiolectasias de tracción, panalización) se evaluaran en tres zonas de cada pulmón (superior, medio e inferior). La extensión de cada hallazgo radiológico será estimado en porcentaje visualmente con respecto a la zona parenquimatosa de cada área analizada. La media de las seis áreas determinará el score total de fibrosis para cada paciente. El TACAR tórax realizado a los 6 meses se analizará de la misma forma y se realizará el análisis de los cambios en cada área escrutada. Este cálculo manual se correlacionará al final del estudio con el cálculo automático a través del sistema CALIPER (en IDIBELL) a partir de los CD anonimizados recibidos de cada paciente incluido.
    o Incidencia de efectos adversos asociados al fármaco (naturaleza, gravedad, frecuencia, causalidad, consecuencia clínica y tiempo desde inicio fármaco) incluyendo nausea, diarrea, dolor abdominal, vómito, cefalea, hipertransaminasemia.
    o Discontinuación del tratamiento o del estudio.
    o % de casos con progresión de fibrosis pulmonar (descenso de CVF ≥ 10% y/o de la DLCO ≥ 15% y/o aparición de imágenes en panal en el TACAR tórax cuando previamente no existía).
    o Capacidad de ejercicio (mejora en % saturación de oxígeno al final de la prueba de caminata 6 minutos o incremento de los metros recorridos mayor a 50 metros)
    o Disminución del requerimiento de oxígeno para hacer actividad física
    o Mejora en la calidad de vida (diferencia en la puntuación final del K-BILD mayor de 5)
    o Hospitalizaciones o visitas urgentes (a Urgencias o Hospital de Día) de causa respiratoria (infección, agudización, complicaciones post-COVID19)
    o Transplante pulmonar o muerte
    E.5.2.1Timepoint(s) of evaluation of this end point
    The assessment of the secondary point is at 6 months.
    La valoración de la variable secundaria es a los 6 meses.
    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 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 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 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 concerned8
    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
    LPLV
    LPLV
    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 months14
    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: 148
    F.1.3Elderly (>=65 years) No
    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 state148
    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)
    The patient's participation in the project will end at the end of the last scheduled visit, with a subsequent month of follow-up.
    La participación de los pacientes en el proyecto finalizará al acabar la última visita prevista, con un mes posterior de seguimiento
    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 Decision2020-07-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-17
    P. End of Trial
    P.End of Trial StatusOngoing
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