| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Idiopathic Pulmonary Fibrosis (IPF) |
| fibrosis pulmonar idiopática (FPI) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary fibrosis is a respiratory disease in which scars are formed in the lung tissues, which leads to breathing problems |
| La fibrosis pulmonar es una enfermedad respiratoria en la que se forman cicatrices en los tejidos pulmonares, lo que conduce a problemas respiratorios |
|
| 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 |
| Proportion of patients who complete 24 weeks of combination treatment on pirfenidone at a dose of 1602?2403 milligrams/day (mg/d) and nintedanib at a dose of 200?300 mg/d |
| Proporción de pacientes que completen 24 semanas de tratamiento combinado con pirfenidona en una dosis de 1602-2403 mg/día y nintedanib en una dosis de 200-300 mg/día. |
|
| E.2.2 | Secondary objectives of the trial |
?Proportion of patients who discontinue pirfenidone, nintedanib, or both study treatments because of adverse events before the Week 24 Visit
?Total number of patient days of combination treatment with pirfenidone at a dose of 1602?2403 mg/d and nintedanib at a dose of 200?300 mg/d
?Total number of days from the initiation of combination treatment to discontinuation of pirfenidone, nintedanib, or both study treatments
?Frequency and timing of adverse events (AE) and serious adverse events (SAEs) |
?Proporción de pacientes que suspendan el tratamiento con pirfenidona, nintedanib o ambos fármacos por acontecimientos adversos antes de la visita de la semana 24.
?Número total de días-paciente de tratamiento combinado con pirfenidona en una dosis de 1602-2403 mg/día y nintedanib en una dosis de 200-300 mg/día.
?Número total de días transcurridos entre el comienzo del tratamiento combinado y la suspensión del tratamiento con pirfenidona, nintedanib o ambos fármacos.
?Frecuencia y cronología de los acontecimientos adversos (AA) y acontecimientos adversos graves (AAG). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
?Male or female, and age 40 through 80 years old
?At the start of screening, on pirfenidone for at least 16 weeks and on a stable dose for at least 28 days (in this study, a stable dose will be defined as 1602?2403 mg/d); the dose must be expected to remain in that range throughout the study
?Documented diagnosis of IPF, per the Investigator per using the criteria of the 2011 American Thoracic Society / European Respiratory Society / Japanese Respiratory Society / Latin American Thoracic Association guidelines
?Pulmonary function test results at screening, percent predicted forced vital capacity (FVC) >=50% and percent predicted carbon monoxide diffusing capacity (DLco) >= 30%
?For women of childbearing potential: agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of < 1% per year, during the treatment period and for at least 3 months after the final Follow-up Visit
?For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm during the treatment period and for at least for at least 3 months after the final Follow-up Visit |
-Varón o mujer y edad comprendida entre los 40 y 80 años.
-Al comienzo de la fase de selección, recepción de pirfenidona durante un mínimo de 16 semanas y recepción de una dosis estable (en este estudio se entenderá por ?dosis estable? una dosis de 1602-2403 mg/día) durante al menos 28 días; previsión de mantener la dosis dentro de ese intervalo durante todo el estudio.
-Diagnóstico documentado de FPI, según el investigador y conforme a los criterios de las directrices de 2011 de la ATS/ERS/JRS/ALAT.
-Valores siguientes de los resultados de las pruebas de función respiratoria, porcentaje de la CVF teórica ? 50%, Porcentaje de la DLco (o capacidad de transferencia del monóxido de carbono convertida en DLco) teórica ? 30%.
-En las mujeres en edad fértil: compromiso de practicar abstinencia (abstenerse de mantener relaciones heterosexuales) o utilizar dos métodos anticonceptivos adecuados, incluido al menos uno con una tasa de fracasos < 1% anual, durante el período de tratamiento y hasta al menos 3 meses después de la visita de seguimiento final.
-En los varones: compromiso de practicar abstinencia (abstenerse de mantener relaciones heterosexuales) o uso de métodos anticonceptivos y compromiso de abstenerse de donar semen hasta al menos 3 meses después de la visita de seguimiento final. |
|
| E.4 | Principal exclusion criteria |
- Clinical evidence of active infection
?In the 28 days before the start of screening, any new or ongoing moderate or severe adverse reaction considered by the Investigator to be related to pirfenidone, or an pirfenidone treatment interruption > 7 days for any reason
?Any condition that is likely to result in death in the 12 months after the start of screening
?Lung transplantation anticipated in the 12 months after the start of screening
?Known hypersensitivity to the active substance or any excipient of either pirfenidone or nintedanib
?Severe hepatic impairment, including end-stage liver disease
?Severe renal impairment, including end-stage renal disease requiring dialysis
?History or risk of gastrointestinal (GI) tract perforation
?History of unstable or deteriorating cardiac or pulmonary disease in the 6 months before the start of screening
?Electrocardiogram (ECG) with a heart-rate?corrected QT interval ? 500 milliseconds (ms) at screening, or a family or personal history of long QT syndrome
?Bleeding risk: genetic predisposition to bleeding, a hemorrhagic event in the 12 months before the start of screening, or abnormal laboratory coagulation parameters. Patients who require fibrinolysis, full-dose therapeutic anticoagulation, high-dose antiplatelet therapy, or other therapy that may substantially increase bleeding risk are excluded
?Use of strong CYP1A2 inhibitors, P-glycoprotein or CYP3A4 or their inducers in the 28 days before the start of screening
?History of alcohol or substance abuse in the 2 years before the start of screening
?Use of any tobacco product in the 12 weeks before the start of screening, or an unwillingness to abstain from their use through the final Follow-up Visit |
- Datos clínicos de infección activa..
-En los 28 días previos al comienzo de la fase de selección, cualquier reacción adversa moderada o intensa nueva o persistente que el investigador considere relacionada con pirfenidona o bien una interrupción del tratamiento con pirfenidona durante más de 7 días por cualquier motivo.
-Cualquier trastorno que es probable que cause la muerte en los 12 meses siguientes al comienzo de la fase de selección.
-Trasplante de pulmón previsto durante los 12 meses siguientes al comienzo de la fase de selección.
-Hipersensibilidad conocida al principio activo o a cualquiera de los excipientes de pirfenidona o nintedanib.
-Insuficiencia hepática grave, incluida una hepatopatía terminal.
-Insuficiencia renal grave incluida una nefropatía terminal con necesidad de diálisis.
-Antecedentes o riesgo de perforación digestiva.
-Antecedentes de cardiopatía o neumopatía (aparte de la FPI) inestable o en situación de deterioro en los 6 meses previos al comienzo de la fase de selección.
-Electrocardiograma (ECG) con un intervalo QT corregido por la frecuencia cardíaca (corregido con la fórmula de Fridericia, QTcF) ? 500 ms en la fase de selección o antecedentes familiares o personales de síndrome del QT largo.
-Riesgo de hemorragia: predisposición genética a la hemorragia, episodio hemorrágico en los 12 meses previos al comienzo de la fase de selección o parámetros de coagulación anormales. Quedarán excluidos los pacientes que requieran fibrinólisis, anticoagulación terapéutica en dosis plenas , tratamiento antiagregante en dosis altas u otro tratamiento que pueda aumentar sustancialmente el riesgo de hemorragia.
-Uso de inhibidores potentes de la enzima CYP1A2 (por ejemplo, fluvoxamina o enoxacino) en los 28 días previos al comienzo de la fase de selección.
-Antecedentes de alcoholismo o toxicomanía en los 2 años previos al comienzo de la fase de selección.
-Uso de cualquier producto derivado del tabaco en las 12 semanas previas al comienzo de la fase de selección o falta de disposición a abstenerse de consumirlo hasta la visita de seguimiento final. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ?Proportion of patients who complete 24 weeks of combination treatment on pirfenidone at a dose of 1602?2403 mg/d and nintedanib at a dose of 200?300 mg/d |
| Proporción de pacientes que completen 24 semanas de tratamiento combinado con pirfenidona en una dosis de 1602-2403 mg/día y nintedanib en una dosis de 200-300 mg/día. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| ?Up to 24 weeks |
| ?Hasta la semana 24. |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of patients who discontinue pirfenidone, nintedanib, or both study treatments because of adverse events before the Week 24 Visit
2. Total number of patient days of combination treatment with pirfenidone and nintedanib
3. Total number of days from the initiation of combination treatment to discontinuation of pirfenidone, nintedanib, or both study treatments
4. Incidence of adverse events (AE) and Serious Adverse Events (SAEs) |
1.Proporción de pacientes que suspendan el tratamiento con pirfenidona, nintedanib o ambos fármacos por acontecimientos adversos antes de la visita de la semana 24.
2.Número total de días-paciente de tratamiento combinado con pirfenidona y nintedanib.
3.Número total de días transcurridos entre el comienzo del tratamiento combinado y la suspensión del tratamiento con pirfenidona, nintedanib o ambos fármacos.
4. Incidencia de acontecimientos adversos (AA) y acontecimientos adversos graves (AAG). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. Up to 24 weeks
4. Up to 35 days after completion of combination treatment (approximately 30 weeks) |
1-3. Hasta la semana 24.
4. Hasta 35 días después de la finalización del tratamiento combinado (aproximadamente 30 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 | No |
| E.6.4 | Safety | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability |
| Tolerabilidad |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Canada |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of this study is defined as the date when the last patient, last visit (LPLV) occurs. LPLV is expected to occur in the 4th quarter of 2017. |
| El final del estudio se define como la fecha en que tenga lugar la última visita del último paciente (UVUP). Se espera que la UVUP se produzca en el cuarto trimestre de 2017. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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