| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| pulmonary hypertension associated with idiopathic interstitial pneumonias |
| hipertensión pulmonar asociada a neumonías intersticiales idiopáticas |
|
| E.1.1.1 | Medical condition in easily understood language |
| high blood pressure in the blood vessels of the lungs associated with interstitial pneumonias of unknown cause |
| presión sanguínea elevada en los vasos sanguíneos de los pulmones asociada a neumonías intersticiales de causa desconocida |
|
| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037406 |
| E.1.2 | Term | Pulmonary hypertension secondary |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy and safety of 26-weeks of treatment with riociguat vs. placebo in patients with symptomatic PH associated with IIP |
| Evaluar la eficacia y la seguridad del tratamiento con riociguat durante 26 semanas frente a placebo, en pacientes con HP sintomática asociada a NII. |
|
| E.2.2 | Secondary objectives of the trial |
Time to clinical worsening as evidenced by the first of any of the following four events:
*All-cause mortality
*Worsening of WHO functional class.
*Need for hospitalization due to worsening cardiopulmonary status, attributable to progression of disease (including but not limited to increased shortness of breath or increased leg swelling)
*15% decrease in the 6MWD test |
el primero de uno de los cuatro acontecimientos siguientes:
*Mortalidad por cualquier causa
*Necesidad de hospitalización por un empeoramiento del estado cardiopulmonar, atribuible a la progresión de la enfermedad (incluido pero no limitado a un aumento de la disnea o un aumento del edema de las extremidades inferiores, entre otros)
*Disminución del 15 % en la PM6M respecto al periodo basal
*Empeoramiento de la clase funcional de la OMS |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men or women aged from >=18 to <=80 years
2. Diagnosed with one of the following (confirmed using a multidisciplinary approach, as per ATS/ERS/JRS/ALAT guidelines [1]):
-Major IIPs diagnosis or suspected as one of the following:
* Idiopathic pulmonary fibrosis
* Idiopathic nonspecific interstitial pneumonia
* Respiratory bronchiolitis-interstitial lung disease
* Desquamative interstitial pneumonia
* Cryptogenic organizing pneumonia
* Acute interstitial pneumonia
-Rare IIPs diagnosis by one of the following:
* Idiopathic lymphoid interstitial pneumonia
* Idiopathic pleuroparenchymal fibroelastosis
-Unclassifiable idiopathic interstitial pneumonias
3. FVC >= 45 %
4. 6MWD >= 150 m to <= 450 m (under stable O2 supplementation via nasal cannula)
5. Diagnosis of PH confirmed by right heart catheter (RHC) with mPAP >= 25 mmHg and PAWP <=15 mmHg at rest
6. Systolic blood pressure (SBP) >= 95 mmHg and no signs or symptoms of hypotension
7. WHO functional class II-IV
8. Women of childbearing potential can only be included in the study if a pregnancy test is negative. Women of childbearing potential and all non-vasectomized male participants must agree to use adequate contraception when sexually active. "Adequate contraception" is defined as any combination of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). Adequate contraception is required from the signing of the informed consent form up until 6 weeks after the last study drug administration |
1. Varones o mujeres de edades comprendidas entre >= 18 y <= 80 años
2. Uno de los siguientes diagnósticos (confirmado con una aproximación multidisciplinar, de acuerdo a las directrices ATS/ERS/JRS/ALAT[1]):
*Diagnóstico o sospecha de NII principales , como una de las siguientes:
*Fibrosis pulmonar idiopática
*Neumonía intersticial no específica idiopática
*Bronquiolitis respiratoria - enfermedad pulmonar intersticial
*Neumonía intersticial descamativa
*Neumonía organizada criptogénica
*Neumonía intersticial aguda
- Diagnóstico de NII rara por una de las siguientes:
*Neumonía intersticial linfoide idiopática
*Fibroelastosis pleuroparenquimatosa idiopática
- Neumonías intersticiales idiopáticas inclasificables
3. Capacidad vital forzada (FVC) >= 45 %
4. Distancia en la prueba de la marcha de seis minutos (6MWD: Six-minute walking distance) >= 150 m a <= 450 m (con administración estable de O2 mediante cánula nasal)
5. Diagnóstico de HP confirmado por cateterismo cardíaco derecho (CCD) con PAPm >= 25 mm Hg y presión de enclavamiento capilar pulmonar (PCWP) <= 15 mm Hg en reposo
6. Presión arterial sistólica (PAS) >= 95 mm Hg y sin signos ni síntomas de hipotensión
7. Clase funcional de la OMS II - IV
8. Sólo se podrán incluir a las mujeres potencialmente fértiles si obtienen un resultado negativo en una prueba de embarazo. Las mujeres potencialmente fértiles y los hombres no sometidos a vasectomía deberán aceptar la adopción de medidas anticonceptivas apropiadas cuando sean sexualmente activos. Un «método anticonceptivo aceptable» se define como cualquier combinación de al menos dos métodos anticonceptivos eficaces, de los que al menos uno debe ser una barrera física (p. ej., preservativos con métodos anticonceptivos hormonales o implantes, o métodos anticonceptivos orales combinados, o determinados dispositivos intrauterinos). Los métodos anticonceptivos adecuados son necesarios a partir del momento de la firma del formulario de consentimiento informado hasta seis semanas después de la última administración del fármaco del estudio |
|
| E.4 | Principal exclusion criteria |
1. Known significant left heart disease:
- Pulmonary venous hypertension indicated by baseline pulmonary capillary wedge pressure > 15 mmHg
- Symptomatic coronary artery disease
- Systolic left-ventricular dysfunction with an left ventricular ejection fraction (LVEF) <45%
2. Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization
3. Any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening. Massive hemoptysis being defined as acute bleeding >240 mL in a
24-hour period or recurrent bleeding >100 mL/d over several days
4. History of acute lung infection or acute exacerbation prior to screening
5. Reasonable likelihood of receiving a lung transplant within the 26 week main study period
6. Pulmonary veno-occlusive disease
7. Difference > 15% between the eligibility and the baseline 6MWD test
8. Saturation of peripheral oxygen (SpO2) remains < 92 % with not more than 6 L of supplemental oxygen at rest
9. Forced expiratory volume in one second (FEV1)/FVC <0.65 after bronchodilator administration
10. CO2 > 45 mmHg
11. Other known cause of ILD including:
a. connective tissue disease
b. sarcoidosis
c. chronic hypersensitivity pneumonitis
d. significant environmental exposure likely to be the cause of the patients ILD (such as asbestos or silica exposure)
12. Extent of emphysema greater than the extent of fibrotic changes (honeycombing, reticular changes) on HRCT scan
13. Use of cytotoxic, immunosuppressive, cytokine modulating therapy initiated within and including 3 months prior to screening or if used systemically e.g. azathioprine, cyclophosphamide, corticosteroids, etanercept, tumor necrosis factor alpha (TNF alpha) inhibitors and others
14. Pirfenidone and any other drug approved specifically for IPF initiated within 3 months prior to screening
15. Any specific treatment for PAH/PH within 3 months prior to screening
16. Active smoking of tobacco of any type or quantity
17. Active participation in a Pulmonary Rehabilitation program, defined as a structured exercise and rehabilitation program supervised by a physician, respiratory therapist and/or a physiotherapist. Patients who have completed a course of Pulmonary Rehabilitation and are in the maintenance phase of the program are eligible for study enrollment
18. Concomitant use of the following medication: nitrates or NO donors (such as amyl nitrite) in any form, phosphodiesterase 5 inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE) inhibitors (theophylline, dipyridamole),
19. Severe hepatic impairment (Child Pugh C)
20. Creatinine clearance < 15 ml/min or on dialysis
21. Pregnant women (i.e. positive pregnancy test or other signs of pregnancy), or breast feeding women, or women of childbearing potential not using adequate contraception (as defined in the aforementioned inclusion criterion) and not willing to agree to 4-weekly pregnancy testing from Visit 1(first administration of study drug) onwards until 6 weeks after last study drug intake
22. Previous randomization to treatment during this study
23. Participation in another clinical study with an investigational drug or a medical device within 30 days prior to randomization (phase I-III clinical studies)
24. Active neurologic, orthopedic or musculoskeletal disorder that is likely to affect performance of the 6MWD test |
1. Cardiopatía izquierda importante conocida:
- Hipertensión venosa pulmonar indicada por una presión de enclavamiento capilar pulmonar basal > 15 mm Hg
- Arteriopatía coronaria sintomática
- Disfunción ventricular izquierda sistólica con fracción de eyección ventricular izquierda (LVEF) < 45 %
2. Estado activo de hemoptisis o hemorragia pulmonar, incluidos los acontecimientos tratados con embolización arterial bronquial
3. Antecedentes de embolización arterial bronquial o hemoptisis masiva en los tres meses previos a la selección. Hemoptisis masiva definida como hemorragia aguda > 240 ml en un período de 24 horas o hemorragia recurrente > 100 ml/d durante varios días
4. Antecedentes de infección pulmonar aguda o exacerbación aguda antes de la selección
5. Probabilidad razonable de recibir un trasplante pulmonar en las 26 semanas del período del estudio principal
6. Enfermedad venooclusiva pulmonar
7. Diferencia > 15 % entre la PM6M de la selección y la PM6M basal
8. Saturación de oxígeno periférico (SO2) permanece en < 92 % con un máximo de 6 l de oxigenoterapia en reposo
9. Volumen espiratorio forzado en el primer segundo (FEV1)/FVC < 0,65 después de la administración de un broncodilatador
10. CO2 > 45 mm Hg
11. Otras causas conocidas de EPI, tales como:
a. enfermedad del tejido conectivo
b. sarcoidosis
c. neumonitis por hipersensibilidad crónica
d. pacientes con EPI que tenga como causa probable una exposición ambiental considerable (como exposición al sílice o al amianto)
12. Grado de enfisema superior al grado de alteraciones fibróticas (panal de abejas, cambios reticulares) según TCAR
13. Uso de tratamiento citotóxico, inmunosupresor y modulador de citocinas, iniciado durante los tres meses previos a la selección, o, si se usan de forma sistémica, por ejemplo, de azatioprina, ciclofosfamida, corticosteroides, etanercept, inhibidores del factor de necrosis tumoral alfa (TNF alfa) u otros
14. Pirfenidona y cualquier otro fármaco autorizado específicamente para la FPI iniciado druante los 3 meses previos la selección
15. Cualquier tratamiento específico para HAP/HP iniciado durante los tres meses previos a la selección
16. Tabaquismo activo de cualquier tipo y en cualquier cantidad
17. Participación activa en un programa de rehabilitación pulmonar, definido como un programa de ejercicios estructurados y de rehabilitación, supervisado por un médico, terapeuta respiratorio y/o fisioterapeuta. Los pacientes que hayan finalizado un ciclo de rehabilitación pulmonar y estén en la fase de mantenimiento del programa son elegibles para su inclusión en el estudio
18. Uso concomitante de los medicamentos que se citan a continuación: nitratos o donadores de NO (como nitrito de amilo) en cualquiera de sus formas, inhibidores de la fosfodiesterasa 5 (como sildenafilo, tadalafilo, vardenafilo) e inhibidores de la fosfodiesterasa (PDE) inespecíficos (teofilina, dipiridamol),
19. Insuficiencia hepática grave (Child Pugh C)
20. Aclaramiento de creatinina < 15 ml/min o en diálisis
21. Mujeres embarazadas (es decir, prueba de embarazo positiva u otros signos de embarazo), o en periodo de lactancia, o que puedan quedarse embarazadas y no utilicen métodos anticonceptivos adecuados (tal como se define en los criterios de inclusión mencionados) y no estén dispuestas a someterse a una prueba de embarazo cada cuatro semanas a partir de la visita 1 (primera administración del fármaco del estudio) hasta seis semanas después de la última administración del fármaco del estudio
22. Aleatorización previa al tratamiento durante este estudio
23. Participación en otro estudio clínico con un fármaco o un producto sanitario en investigación en los 30 días previos a la aleatorización (estudios clínicos de fase I-III)
24. Trastorno neurológico, traumatológico o locomotor activo que es probable que afecte la capacidad para realizar la PM6M |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| the mean change in 6 minute walking distance from baseline to week 26 |
| el cambio medio en la PM6M desde el periodo basal hasta la semana 26 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Time to clinical worsening as evidenced by the first of any of the following four events:
* All-cause mortality
* Need for hospitalization due to worsening cardiopulmonary status, attributable to
progression of disease (including but not limited to increased shortness of breath or
increased leg swelling)
* 15% decrease in the 6MWD test
* Worsening of WHO functional class.
Exploratory efficacy measures
* Time to disease progression as defined by >15% decrease in the 6MWD test or a 10% decrease in the FVC.
* Competing risk analysis based on 50 meter decrease in the 6MWD test, 50 meter increase in the 6MWD test or patients who remain within 50 meters of their baseline 6MWD test.
* Change in DLCO (Hbg corrected) baseline to week 26
* Change in FVC baseline to week 26
* Change in Kco from baseline to week 26
* Change in mPAP, PVR and CI baseline to week 26 (only patients with RHC at baseline and week 26)
* Change in heart rate recovery between 6MWD baseline and week 26. Heart rate recovery calculated by the difference between the heart rate at the end of the 6MWD test and after one minute of recovery.
* Change in dyspnea using the Borg scale baseline to week 26
* Change in resting partial pressure of mixed venous oxygen tension baseline to week 26 (only patients with RHC at baseline and week 26)
* Change in resting oxygen saturation using pulse oximetry (SpO2) baseline to week 26
* Change in venous oxygen saturation (SvO2 ) baseline to week 26 (only patients with RHC at baseline and week 26)
* Change in alveolar-arterial (A-a) gradient baseline to week 26
* Change in quality of life (QoL) (SGRQ) baseline to week 26
* Number of clinical worsenings baseline to week 26
* Number of hospitalizations due to disease progression baseline to week 26
* Number of hospital days between groups.
* All-cause mortality baseline to week 26
* Change in NT-proBNP baseline to weeks 18 and 26
* Change in osteopontin, chemokine CCL18, matrix metalloproteinases MMP7 and MMP9 baseline to weeks 18 and 26
* Evaluation and change in echo parameters from baseline to week 26 Endpoints for the long-term phase (week 26 to study completion)
* Change in 6MWD baseline to week 48 and every 12 weeks thereafter until study completion
* Clinical worsening events to week 48 and every 12 weeks thereafter until study completion
* Time to clinical worsening to week 48 and every 12 weeks thereafter until study completion
* Change in WHO functional class baseline to week 48 and every 12 weeks thereafter until study completion
* Change in dyspnea using the Borg scale from baseline to week 48, and 12 weeks thereafter until study completion
* Change in QoL (SGRQ) baseline to week 48 and every 12 weeks thereafter until study completion |
Tiempo hasta el empeoramiento clínico, determinado por el primero de uno de los cuatro acontecimientos siguientes:
*Mortalidad por cualquier causa
*Necesidad de hospitalización por un empeoramiento del estado cardiopulmonar, atribuible a la progresión de la enfermedad (incluido pero no limitado a un aumento de la disnea o un aumento del edema de las extremidades inferiores, entre otros)
*Disminución del 15 % en la PM6M respecto al periodo basal
*Empeoramiento de la clase funcional de la OMS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Belgium |
| Canada |
| France |
| Italy |
| Japan |
| Australia |
| Germany |
| Spain |
| Switzerland |
| United Kingdom |
| 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
|
| LVLS |
| ultimo paciente ultima visita |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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