E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | |
E.1.1.1 | Medical condition in easily understood language |
idiopathic pulmonary fibrosis |
Fibrosis pulmonar idiopática |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10021240 |
E.1.2 | Term | Idiopathic pulmonary fibrosis |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the trial will be to assess the effect of nintedanib on rate of change in extracellular matrix (ECM) turnover biomarker CRPM over 12 weeks which has shown to strongly associate with disease progression in patients with IPF in the PROFILE cohort. |
Evaluar el efecto de nintedanib en varios tipos de biomarcadores de recambio de la matriz extracelular (MEC) y el valor predictivo del cambio en estos biomarcadores de MEC sobre la progresión de la enfermedad. |
|
E.2.2 | Secondary objectives of the trial |
A secondary objective is to confirm the observed results from the PROFILE cohort, i.e. to assess the predictive value of change in extracellular matrix (ECM) biomarkers CRPM, C1M and C3M over 12 weeks for disease progression as defined by FVC decline ?10% or death over 52 weeks. |
Un objetivo secundario es confirmar los resultados observados del perfil cohorte,p ej, evaluar el valor predictivo del cambio en los biomarcadores de MEC (CRPM, C1M y C3M) durante 12 semanas sobre la progresión de la enfermedad definido como descenso de la FVC ?10% o muerte tras 52 semanas |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Written informed consent consistent with ICH-GCP and local laws, signed prior to participation in the trial including any study related procedures being performed; - Male or female patients aged =40 years at Visit 1; - A clinical diagnosis of IPF within the last 3 years from visit 0, based upon the ATS/ERS/JRS/ALAT 2011 guideline; - Chest high resolution computed tomography (HRCT) scan performed within 18 months of Visit 0; - Combination of HRCT pattern, and surgical lung biopsy pattern (the latter if available) as assessed by central review are consistent with the diagnosis of IPF; - FVC =80% of predicted normal at Visit 1. |
-Consentimiento informado escrito siguiendo la normativa local, firmado antes de la participación en el ensayo. -Pacientes varones o mujeres con edad ? 40 años en la visita 1 -Diagnóstico clínico de IPF en función de la guía ATS/ERS/JRS/ALAT 2011 en los 3 años previos a la visita 0 -HRCT realizada en los 18 meses previos a la visita 0 -Confirmación del diagnóstico mediante revisión central de la HRCT torácica y biopsia pulmonar quirúrgica (la más reciente si está disponible) previa a la aleatorización -FVC ? 80 % del valor teórico de referencia en la visita 1 (selección). |
|
E.4 | Principal exclusion criteria |
- ALT, AST > 1.5 fold upper limit of normal (ULN) at visit 1; - Total bilirubin > 1.5 fold ULN at visit 1; - Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment); - Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC <0.7 at visit 1); - History of myocardial infarction within 6 months of visit 1 or unstable angina within 1 month of visit 1; - Bleeding Risk: -- Known genetic predisposition to bleeding; -- Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin etc.) or high dose antiplatelet therapy; -- History of haemorrhagic central nervous system (CNS) event within 12 months prior to visit 1; -- History of haemoptysis or haematuria, active gastro-intestinal bleeding or ulcers and/or major injury or surgery within 3 months prior to visit 1; -- International normalised ratio (INR) > 2 at visit 1; -- Prothrombin time (PT) and partial thromboplastin time (PTT) > 150% of ULN at visit 1; - Planned major surgery during the trial participation, including lung transplantation, major abdominal or major intestinal surgery; - History of thrombotic event (including stroke and transient ischemic attack) within 12 months of visit 1; - Creatinine clearance < 30 mL/min calculated by Cockcroft-Gault formula at Visit 1; - Treatment with nintedanib, pirfenidone, azathioprine, cyclophosphamide, cyclosporine, any other investigational drug, n-acetylcysteine, prednisone/prednisolone >15 mg daily or >30 mg every 2 days OR use of other systemic corticosteroids as well as other investigational drugs within 4 weeks of visit 2; - Known hypersensitivity to nintedanib, peanut, soya or to any other components of the study medication; - Prior discontinuation of nintedanib treatment due to intolerability/ adverse events considered drug related; - A disease or condition which in the opinion of the investigator may interfere with testing procedures or put the patient at risk when participating in this trial; - Alcohol or drug abuse which in the opinion of the treating physician would interfere with the treatment and would affect patient's ability to participate in this trial; - Patients not able to understand and follow study procedures such as but not limited to home spirometry, including completion of self-administered questionnaires without help; - Women who are pregnant, nursing, who plan to become pregnant while in the trial or female patients with positive ß-HCG test at visit 1 and/or visit 2; - Women of childbearing potential not willing or able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly; - Patients with acute IPF exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period. Visit 1 and/or Visit 2 should be postponed in case of an IPF exacerbation or respiratory tract infection. Refer to Section 6.1 for information on re-scheduling of visits; - Patients who are currently participating in another trial or who have been participating in another trial within one month prior to Visit 1, and patients who have previously been enrolled in this trial. |
-ALT, AST > 1,5 veces el límite superior de la normalidad (ULN) en la visita 11. -Bilirrubina total > 1,5 veces el ULN en la visita 11. -Pacientes con enfermedad hepática crónica subyacente (Child Pugh A, B o C). -Obstrucción de las vías respiratorias relevante (es decir, FEV1/FVC < 0,70 antes de la broncodilatación [es decir, 70 %] en la visita 1). -Antecedentes de infarto de miocardio en los 6 meses previos a la visita 1 o angina de pecho inestable durante el mes previo a la visita 1. -Riesgo de hemorragia: ? Predisposición hemorrágica genética conocida. ? Pacientes que requieren fibrinólisis, dosis completa de tratamiento terapéutico anticoagulante (p. ej., antagonistas de la vitamina K, inhibidores directos de la trombina, heparina, hirudina, etc.) o un tratamiento antiagregante plaquetario en dosis altas2. ? Antecedentes de un episodio hemorrágico del sistema nervioso central (CNS) en los 12 meses previos a la visita 1. ? Antecedentes de hemoptisis o hematuria, hemorragia gastrointestinal activa o úlceras y/o lesión grave o cirugía en los 3 meses anteriores a la visita 1. ? Índice internacional normalizado (INR) > 2 en la visita 11. ? Tiempo de protrombina (PT) y tiempo de tromboplastina parcial (PTT) > 150 % del ULN en la visita 11. -Cirugía mayor3 programada durante la participación en el estudio, incluyendo trasplante pulmonar, cirugía abdominal o intestinal mayores. -Antecedentes de episodio trombótico (incluido ictus y accidente isquémico transitorio) en los 12 meses previos a la visita 1. -Aclaramiento de creatinina < 30 ml/min calculado según la fórmula de Cockcroft?Gault visita 1 (anexo 10.2). -Tratamiento con nintedanib, pirfenidona, azatioprina, ciclofosfamida, ciclosporina, cualquier otro producto en investigación, n-acetilcisteína, prednisona/prednisolona > 15 mg al día o > 30 mg cada 2 días O uso de otros corticosteroides sistémicos, así como cualquier otro fármaco en investigación en las 4 semanas previas a la visita 2. -Hipersensibilidad conocida a nintedanib, a los cacahuetes, a la soja o a cualquier otro componente de la medicación del estudio. -Suspensión del tratamiento con nintedanib en el pasado debido a intolerabilidad/acontecimientos adversos considerados como relacionados con el fármaco. -Enfermedad o afección que, en opinión del investigador, pueda interferir con los procedimientos del estudio o poner al paciente en riesgo al participar en este estudio. -Alcoholismo o toxicomanía que, en opinión del médico encargado del tratamiento, podrían interferir con el tratamiento y podrían afectar a la capacidad del paciente para participar en este estudio. -Pacientes que no pueden comprender y seguir los procedimientos del estudio, entre otras la espirometría domiciliaria6, incluida la cumplimentación sin ayuda de los cuestionarios que deben rellenar los propios pacientes. -Mujeres embarazadas, en periodo de lactancia o que prevean quedarse embarazadas durante el periodo del estudio o mujeres con una prueba de embarazo (ß-HCG) positiva en la visita 1 y/o en la visita 2. Pacientes con reagudización de la IPF o cualquier infección de las vías respiratorias en las cuatro semanas previas a la visita 1 o durante el periodo de selección.
La visita 1 y/o la visita 2 deberán posponerse en caso de reagudización de la IPF o infección de las vías respiratorias. Véase el apartado 6.1 para obtener información sobre la reprogramación de visitas. Pacientes que estén participando o hayan participado en otro estudio con fármaco(s) en investigación en el mes anterior a la visita 1 y pacientes incluidos con anterioridad en este estudio. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1: The rate of change (slope) in blood CRPM from baseline to week 12. |
Tasa de cambio (pendiente) en la CRPM sanguínea desde el periodo basal hasta la semana 12. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1: 12 weeks |
1: 12 semanas |
|
E.5.2 | Secondary end point(s) |
The key secondary endpoint 1: Proportion of patients with disease progression as defined by absolute FVC (% predicted) decline ?10% or death until week 52 based on in clinic supervised spirometry.
Secondary endpoints: 2: Rate of change (slope) in blood C1M from baseline to week 12 3: Rate of change (slope) in blood C3M from baseline to week 12. |
Criterio de valoración secundario fundamental: 1: Porcentaje de pacientes con progresión de la enfermedad definida por una reducción de la FVC absoluta (porcentaje del valor teórico de referencia) ? 10 % o muerte hasta la semana 52.
Criterios secundarios de valoración: 2:Tasa de cambio (pendiente) en el C1M sanguíneo desde el periodo basal hasta la semana 12. 3:Tasa de cambio (pendiente) en el C3M sanguíneo desde el periodo basal hasta la semana 12. Otros criterios de valoración (seleccionados): ? Tasa de cambio (pendiente) en la CRPM, el C1M y el C3M desde la semana 12 a la semana 52. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: 52 weeks 2: 12 weeks 3: 12 weeks |
1: 52 semanas 2: 12 semanas 3: 12 semanas |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Japan |
Korea, Republic of |
United States |
|
E.8.7 | Trial 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.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 11 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 27 |