Short-term Survival of Subjects With Acute-on-chronic Liver Failure After Plasma Exchange With Human Serum Albumin 5%

Approximately 380 subjects with cirrhosis, ACLF, and high risk of hospital mortality
(ACLF-1b, ACLF-2, or ACLF-3a) will be included in this study after obtaining written informed
consent. In case of hepatic encephalopathy (HE), written informed consent will be obtained
from a relative or a legally authorized representative (surrogate).

Randomization of subjects will be stratified by region (European Union [EU] or North America
[NA]) and the 3 ACLF grades (ACLF-1b, ACLF-2, or ACLF-3a). Within each stratum (ie, each
unique combination of region and ACLF grade), subjects will be randomized in a 1:1 ratio into
2 treatment groups below:

- SMT+PE-A 5% (treatment group)

- SMT (control group)

SMT + PE-A 5% Treatment Group:

PE-A 5% will be performed using 5% albumin (Albutein® 5%) as the main replacement fluid
administered intravenously. Fresh frozen plasma (FFP) will be given after each PE-A 5%
session to prevent coagulopathy.

The exact number of sessions will be determined by the pattern of response (achieving
complete response or no improvement/deterioration of ACLF) to PE-A 5% therapy. IVIGs will be
administered to prevent the development of hypogammaglobulinemia and infection.

SMT Control Group:

The Treatment Period will be 7 days for all subjects and will be prolonged depending on
subject's ACLF evolution to up to 17 days.

Subjects in both the SMT+ PE-A 5% treatment group and the SMT control group will be followed
for 90 days after randomization. During the entire study, the safety of both groups will be
monitored by a Data Safety Monitoring Board.

Inclusion Criteria:

- A subject must meet all the following inclusion criteria to be eligible for
participation in this study:

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 HE, informed consent will be provided by a relative or a legally
authorized representative (surrogate).

Exclusion Criteria:

- A subject meeting any of the following exclusion criteria is NOT eligible for
participation in the study:

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 (ARDS) with peripheral oxygen
saturation (SpO^2) ≤89.

9. Subjects with active or recent bleeding (unless controlled for >48 hours).

10. Subjects with severe thrombocytopenia (≤20×10^9/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 class III
or IV).

14. Subjects with severe pulmonary disease (Global Obstructive Lung Disease 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.