| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| portal hypertension |
| hipertensión portal |
|
| E.1.1.1 | Medical condition in easily understood language |
| hypertension |
| hipertensión |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036200 |
| E.1.2 | Term | Portal hypertension |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| 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 |
The trial will investigate the safety and tolerability of BI 685509 in patients with CSPH in compensated cirrhosis due to HBV, HCV and NASH with or without T2DM and the combination of BI 685509 and empagliflozin in patients with CSPH in compensated cirrhosis due to NASH with T2DM, on top of standard of care respectively.
The primary objective is to estimate the percentage change in HVPG from baseline measured after 8 weeks. The primary analysis will be made for treated patients with baseline HVPG measurements (Full Analysis Set, FAS) as if all patients took treatment for the duration of the trial. |
El ensayo investigará la seguridad y tolerabilidad del BI 685509 en pacientes con CSPH en cirrosis compensada debida a VHB, VHC y EHNA con o sin DM2 y la combinación de BI 685509 con empagliflozina en pacientes con CSPH en cirrosis compensada debida a EHNA con DM2, además del tratamiento de referencia respectivamente.
El objetivo principal es calcular el cambio porcentual en el GPVH respecto al inicio medido después de 8 semanas. El análisis primario se realizará para los pacientes tratados con medidas iniciales de GPVH (Conjunto de Análisis Completo, FAS) como si todos los pacientes hubieran recibido tratamiento durante el ensayo. |
|
| E.2.2 | Secondary objectives of the trial |
| Safety and tolerability will also be investigated. |
| También se investigará la seguridad y la tolerabilidad. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial
2. Male or female who is ≥ 18 (or who is of legal age in countries where that is greater than 18) and ≤ 75 years old at screening (Visit 1a)
3. Clinical signs of CSPH as described by either one of the points below. Each trial patient must have a gastroscopy during the screening period (Visit 1b) or within 3 months prior to screening (Visit 1b).
- documented endoscopic proof of oesophageal varices and / or gastric varices at
screening (Visit 1b) or within 3 months prior to screening (Visit 1b)
- documented endoscopic-treated oesophageal varices as preventative treatment
4. CSPH defined as baseline HVPG ≥ 10 mmHg (measured at Visit 1c), based on a local interpretation of the pressure tracing
5. Diagnosis of compensated cirrhosis due to HCV, HBV, or NASH with or without T2DM. Diagnosis of cirrhosis must be based on histology (historical data is acceptable) or on clinical evidence of cirrhosis (e.g. platelet count < 150 x 109/L [150 x 103/μL], nodular liver surface on imaging or splenomegaly etc.) Diagnosis of NASH based on either
i. Current or historic histological diagnosis of NASH OR steatosis
OR
ii. Clinical diagnosis of NASH based on historic or current imaging diagnosis of fatty liver (Fibroscan, US, MRI, CT) AND at least 2 current or historic comorbidities of the metabolic syndrome (overweight/obesity, T2DM, hypertension, hyperlipidemia)
6. Willing and able to undergo HVPG measurements per protocol (based on Investigator judgement)
7. If receiving statins must be on a stable dose for at least 3 months prior to screening (Visit 1b), with no planned dose change throughout the trial
8. If receiving treatment with NSBBs or carvedilol must be on a stable dose for at least 3 months prior to screening (Visit 1b), with no planned dose change throughout the trial
Further criteria apply. |
1. Consentimiento informado, firmado y fechado, de conformidad con la ICH-GCP y la legislación local antes de la admisión al ensayo
2. Hombres o mujeres ≥ 18 años (o mayores de edad en los países en los que ésta sea de más de 18 años) y ≤ 75 años en el momento de la selección (Visita 1a)
3. Signos clínicos de HPCS descritos por cualquiera de los siguientes puntos. Cada paciente del ensayo debe someterse a una gastroscopia durante el período de selección (visita 1b) o en los 3 meses anteriores a la selección (visita 1b):
-prueba endoscópica documentada de varices esofágicas y/o varices gástricas en la selección (visita 1b) o en los 3 meses anteriores a la selección (visita 1b)
-varices esofágicas documentadas tratadas mediante endoscopia como tratamiento preventivo
4. HPCS definida por un GPVH ≥ 10 mmHg (medido en la visita 1c), basada en la interpretación local del trazado de la presión
5. Diagnóstico de cirrosis compensada por VHC, VHB, o EHNA con o sin DM2. El diagnóstico de cirrosis debe basarse en la histología (los datos históricos son aceptables) o en signos clínicos de cirrosis (por ejemplo, recuento de plaquetas < 150 x 10^9/L [150 x 10^3/L], superficie hepática nodular en imágenes o esplenomegalia, etc.). Diagnóstico de EHNA basado en:
i. Diagnóstico histológico actual o histórico de EHNA o esteatosis
O
ii. Diagnóstico clínico de EHNA basado en el diagnóstico imagenológico histórico o actual de hígado graso (Fibroscan, US, MRI, CT) Y al menos 2 comorbilidades actuales o históricas del síndrome metabólico (sobrepeso/obesidad, DM2, hipertensión, hiperlipidemia).
6. Disposición y capacidad de someterse a mediciones de GPVH según el protocolo (según el criterio del investigador)
7. Si recibe estatinas deben estar en una dosis estable durante al menos 3 meses antes de la selección (Visita 1b), sin que se prevean cambios de la dosis durante todo el ensayo
8. Si recibe tratamiento con NSBBs o carvedilol deben estar en una dosis estable durante al menos 3 meses antes de la selección (Visita 1b), sin que se prevean cambios de la dosis durante todo el ensayo.
Se aplican más criterios. |
|
| E.4 | Principal exclusion criteria |
1. Previous clinically significant decompensation events (e.g. ascites [more than perihepatic ascites], VH and / or overt / apparent HE)
2. History of other forms of chronic liver disease (e.g. alcohol-related liver disease (ARLD), autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson’s disease, haemachromatosis, alpha-1 antitrypsin [A1At] deficiency)
3. Patients without adequate treatment for HBV, HCV or NASH as per local guidance (e.g. antiviral therapy for chronic HBV or HCV infection or lifestyle modification in NASH)
- if received curative anti-viral therapy for HCV, no sustained virological response (SVR) or SVR sustained for less than 2 years prior to screening or if HCV RNA detectable
- If receiving anti-viral therapy for HBV, less than 6 months on a stable dose prior to screening, with planned dose change during the trial or HBV DNA detectable
- Weight change ≥ 5% within 6 months prior screening
4. Must take, or wishes to continue the intake of, restricted concomitant therapy or any concomitant therapy considered likely (based on Investigator judgement) to interfere with the safe conduct of the trial
5. SBP < 100 mmHg and DBP < 70 mmHg at screening (Visit 1a)
6. Model of End-stage Liver Disease (MELD) score of > 15 at screening (Visit 1a), calculated by the central laboratory
7. Hepatic impairment defined as a Child-Turcotte-Pugh score ≥ B8 at screening (Visit 1a), calculated by the site, using central laboratory results
8. ALT or AST > 5 times upper limit of normal (ULN) at screening (Visit 1a), measured by the central laboratory
Further criteria apply. |
1. Acontecimientos de descompensación clínicamente significativos previos (p. ej. ascitis [más que ascitis perihepática], HDV y/o EH manifiesta)
2. Antecedentes de otras formas de hepatopatía crónica (por ejemplo, enfermedad hepática alcohólica (EHA), enfermedad hepática autoinmune, esclerosis biliar primaria, colangitis esclerosante primaria, enfermedad de Wilson, hemacromatosis, deficiencia de alfa-1 antitripsina [A1At])
3. Pacientes sin tratamiento adecuado para VHB, VHC o EHNA según las directrices locales (por ejemplo, terapia antiviral en infectados crónicos por VHB o VHC o modificación del estilo de vida en EHNA)
- si recibió terapia antiviral curativa para el VHC, sin respuesta virológica sostenida (RVS) o RVS sostenida durante menos de 2 años antes de la detección o si el ARN del VHC es detectable
- si recibe terapia antiviral para el VHB menos de 6 meses en dosis estables antes de la selección, con cambio de dosis planeado durante el ensayo o si el ADN del VHB es detectable
- Cambio de peso ≥ 5% en los 6 meses previos al cribado
4. Debe tomar, o desea continuar con tomando, el tratamiento concomitante restringido o cualquier tratamiento concomitante que se considere probable (según criterio del investigador) que interfiera con la seguridad del ensayo
5. PAS < 100 mmHg y PAD < 70 mmHg en el cribado (visita 1a)
6. Puntuación según el modelo de hepatopatía terminal (MELD) > 15 en la selección (visita 1a), calculada por el laboratorio central
7. Insuficiencia hepática definida como una puntuación de Child-Turcotte-Pugh ≥ B8 en la selección (visita 1a), calculada por el centro, utilizando los resultados del laboratorio central
8. ALT o AST > 5 veces el límite superior de la normalidad (LSN) en la selección (Visita 1a), medido por el laboratorio central
Se aplican más criterios. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1) Percentage change in HVPG from baseline (measured in mmHg) after 8 weeks of treatment |
| 1) Cambio porcentual en el GPVH respecto al inicio (medido en mmHg) después de 8 semanas de tratamiento |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) occurrence of a response, which is defined as > 10% reduction from baseline HVPG (measured in mmHg) after 8 weeks of treatment
2) occurrence of one or more decompensation events (i.e. ascites, VH, and / or overt HE) during the 8-week treatment period
3) occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on Investigator judgement, during the 8-week treatment period
4) occurrence of discontinuation due to hypotension or syncope during the 8-week treatment period |
1) aparición de una respuesta, que se define como una reducción > 10% respecto al GPVH inicial (medido en mmHg) después de 8 semanas de tratamiento
2) aparición de uno o más acontecimientos de descompensación (p. ej. ascitis, hemorragia digestiva por rotura de varices (HDV) y/o encefalopatía hepática (EH) manifiesta) durante el periodo de tratamiento de 8 semanas
3) aparición de hipotensión o síncope de grado 3 según los CTCAE (o superior), según el criterio del investigador, durante el periodo de tratamiento de 8 semanas
4) retirada del tratamiento por hipotensión o síncope durante el periodo de tratamiento de 8 semanas |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 8 weeks
2) 8 weeks
3) 8 weeks
4) 8 weeks |
1) 8 semanas
2) 8 semanas
3) 8 semanas
4) 8 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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.8.1.1 | Randomised | Yes |
| 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 | 4 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 |
| Argentina |
| Canada |
| China |
| Israel |
| Japan |
| Singapore |
| United States |
| Austria |
| France |
| Netherlands |
| Spain |
| Switzerland |
| Germany |
| Italy |
| Belgium |
| Denmark |
| United Kingdom |
|
| 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 |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 9 |
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