E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with cirrhosis with ACLF-1b, ACLF-2, or ACLF-3a detected either at admission or during hospitalization |
Sujetos con cirrosis con ACLF-1b, ACLF-2 o ACLF-3a detectados al ingreso o durante la hospitalización |
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E.1.1.1 | Medical condition in easily understood language |
Subjects with cirrhosis and diagnosed Acute-on-Chronic Liver Failure |
Sujetos con cirrosis y diagnóstico de ACLF |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10077305 |
E.1.2 | Term | Acute on chronic liver failure |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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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 effect of standard medical treatment (SMT) plus PE-A 5% (SMT+PE-A 5%) on 90-day overall survival. |
- Evaluar el efecto del tratamiento médico estándar (TME) más RP-A 5% (TME+RP-A 5%) en la supervivencia global al cabo de 90 días. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of SMT+PE-A 5% on 90-day transplant-free survival.
- To evaluate the effect of SMT+PE-A 5% on 28-day overall survival. |
- Evaluar el efecto del TME+RP-A 5% en la supervivencia libre de trasplante a los 90 días.
- Evaluar el efecto del TME+RP-A 5% en la supervivencia global a los 28 días. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female cirrhotic subjects between 18 and 79 years of age.
2. Subjects with ACLF-1b, ACLF-2, or ACLF-3a detected either at admission or during hospitalization (must be ACLF-1b, -2, or -3a within the Screening Period [a maximum of 10 days])
3. Willing and able to provide written informed consent or have an authorized representative able to provide written informed consent on behalf of the subject in accordance with local law and institutional policy.
4. In case of hepatic encephalopathy, informed consent will be provided by a relative or a legally authorized representative (surrogate). |
1. Hombres o mujeres cirróticos entre 18 y 79 años de edad.
2. Sujetos con ACLF-1b, ACLF-2 o ACLF-3a detectados al ingreso o durante la hospitalización (deben ser ACLF-1b, -2 o -3a dentro del período de selección [un máximo de 10 días]).
3. Los sujetos deben estar dispuestos y ser capaces de proporcionar el consentimiento informado por escrito o tener un representante autorizado capaz que pueda proporcionar el consentimiento informado por escrito en nombre del sujeto según la ley local y la política institucional.
4. En caso de encefalopatía hepática, un familiar o un representante legalmente autorizado (sustituto) proporcionará el consentimiento informado. |
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E.4 | Principal exclusion criteria |
1. Subjects without ACLF.
2. Subjects with ACLF-1a or ACLF-3b after the Screening Period.
3. Subjects fulfilling inclusion criteria that improve to no ACLF or to ACLF-1a or worsen to ACLF-3b during the Screening Period (between initial evaluation and time of randomization).
4. Subjects with ACLF for more than 10 days prior to randomization.
5. Subjects with acute or subacute liver failure without underlying cirrhosis.
6. Subjects with septic shock lasting >1 hour that does not respond to fluid resuscitation-IV therapy or pharmacologic-pressors.
7. Subjects with active bacterial or fungal infection with hemodynamic instability.
8. Subjects with acute respiratory distress syndrome with peripheral oxygen saturation (SpO2) ≤89.
9. Subjects with active or recent bleeding (unless controlled for >48 hours).
10. Subjects with severe thrombocytopenia (≤20×109/L) (based on local laboratory assessment).
11. Subjects with chronic renal failure and currently receiving hemodialysis.
12. Evidence of current locally advanced or metastatic malignancy. Subjects with hepatocellular carcinoma within the Milan criteria (1 nodule ≤5 cm or 3 nodules ≤3 cm, non-melanocytic skin cancer, and controlled breast or prostate cancer can be included).
13. Subjects with severe chronic heart failure (New York Heart Association [NYHA] class III or IV).
14. Subjects with severe pulmonary disease (Global Obstructive Lung Disease [GOLD] stage III or IV).
15. Subjects with severe myopathy as defined clinically.
16. Subjects with a known infection with human immunodeficiency virus (HIV) or have clinical signs and symptoms consistent with current HIV infection.
17. Females who are pregnant, breastfeeding, or if of childbearing potential, unwilling to practice a highly effective method of contraception (oral, injectable, or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, condom, or occlusive cap with spermicidal foam/gel/cream/suppository, male sterilization, or true abstinence*) throughout the study.
* True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception).
18. Subjects with previous liver transplantation.
19. Subjects receiving anti-platelet or anti-coagulant therapy.
20. Participation in another clinical study within at least 30 days prior to screening.
21. Subjects with active drug addiction.
22. Subjects with a do-not-resuscitate order.
23. In the opinion of the investigator, the subject may have compliance problems with the protocol and the procedures of the protocol. |
1. Sujetos sin ACLF.
2. Sujetos con ACLF-1a o ACLF-3b) después del período de selección.
3. Sujetos que cumplan con los criterios de inclusión que mejoran a no ACLF o ACLF-1a o empeoran a ACLF-3b durante el período de selección (entre la evaluación inicial y el momento de asignación al azar).
4. Sujetos con ACLF durante más de 10 días antes de la asignación al azar.
5. Sujetos con insuficiencia hepática aguda o subaguda sin cirrosis subyacente.
6. Sujetos con shock séptico que dure > 1 hora y que no responda a la terapia de reanimación con líquidos-IV ni a los presores farmacológicos.
7. Sujetos con infección bacteriana o micótica activa con inestabilidad hemodinámica.
8. Sujetos con síndrome de dificultad respiratoria aguda con saturación de oxígeno periférico (SPO2) ≤89.
9. Sujetos con sangrado activo o reciente (a menos que se controle durante > 48 horas).
10. Sujetos con trombocitopenia grave (≤20×109/L) (basada en los resultados del laboratorio local).
11. Sujetos con insuficiencia renal crónica y actualmente en hemodiálisis.
12. Evidencia de signos de neoplasia maligna localmente avanzada o metastásica actual. Se pueden incluir sujetos con carcinoma hepatocelular dentro de los criterios de Milán (1 nódulo ≤ 5 cm o 3 nódulos ≤3 cm), cáncer de piel no melanocítico y cáncer de mama o próstata controlado).
13. Sujetos con insuficiencia cardíaca crónica grave (New York Heart Association [NYHA] clase III o IV).
14. Sujetos con enfermedad pulmonar grave (Enfermedad pulmonar obstructiva global [GOLD, por sus siglas en inglés] de grado III o IV).
15. Sujetos con miopatía severa según definición clínica.
16. Sujetos con infección conocida por el virus de la inmunodeficiencia humana (VIH) o que tengan signos y síntomas clínicos compatibles con la infección por el VIH actual.
17. Mujeres que estén embarazadas, en periodo de lactancia o si están en edad fértil, que no estén dispuestas a utilizar un método anticonceptivo altamente eficaz (métodos anticonceptivos hormonales orales, inyectables o implantados, colocación de un dispositivo intrauterino o sistema intrauterino, preservativo o tapón oclusivo con espermicida en espuma/gel/crema/supositorio, esterilización masculina o abstinencia real*) durante todo el estudio.
Abstinencia real: cuando esto está en consonancia con el estilo de vida preferido y habitual del sujeto (la abstinencia periódica [p. ej., los métodos de calendario, de ovulación, sintotérmico o de posovulación], la declaración de abstinencia durante la duración de un ensayo y la marcha atrás no son métodos anticonceptivos aceptables).
18. Sujetos con trasplante hepático previo.
19. Sujetos que reciben terapia antiplaquetaria o anticoagulante.
20. Participación en otro estudio clínico al menos 30 días antes de la selección.
21. Sujetos con drogadicción activa.
22. Sujetos con orden de no resucitar.
23. En opinión del investigador, el sujeto puede tener problemas de cumplimiento del protocolo y los procedimientos del protocolo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is to demonstrate the superiority of SMT+PE-A5% to SMT alone on 90-day overall survival . |
La variable principal de eficacia será el tiempo hasta la muerte durante 90 días después de la asignación al azar de TME+RP-A 5% respecto de TME solo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The effect of SMT+PE-A 5% treatment on 90-day transplant-free survival and on 28-day overall survival versus SMT alone. |
Evaluar los efectos de RP-A 5% en la supervivencia libre de trasplante a los 90 días y la supervivencia global a los 28 días respecto al TME solo. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
28 and 90 days |
28 y 90 días |
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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 | 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) | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard Medical Treatment according to the local guidelines (standard medical care) |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
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 |
Austria |
Belgium |
Denmark |
France |
Germany |
Italy |
Portugal |
Spain |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
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 | 3 |