TRimetazidine for acUte on Chronic Liver Failure STudy

A Phase 1b Open-Label Study Assessing the Pharmacokinetics, Tolerability, and Safety of Oral Trimetazidine in Subjects With Acute-on-Chronic Liver Failure

The study will assess the pharmacokinetics (PK), tolerability, and safety of oral trimetazidine administered to subjects with AD (ACLF Grade 0) or with ACLF Grade 1 or 2.

The study will assess the PK, tolerability, and safety of oral trimetazidine administered to subjects with acute-on-chronic (ACLF) Grades 1 and 2 with liver failure and a range of renal function. Subjects will receive up to 60 mg/day for 28 days.

Two groups of subjects will be enrolled:

Group 1

• AD with serum creatinine ≥ 1 and < 2 mg/dL, OR

• ACLF 1 with

  • liver failure and serum creatinine ≥ 1.5 and < 2 mg/dl, or
  • liver failure and West Haven grade 1-2 hepatic encephalopathy, or
  • coagulation failure and serum creatinine ≥ 1.5 and < 2 mg/dl, or
  • coagulation failure and West Haven grade 1-2 hepatic encephalopathy, OR

• ACLF 2 with

  • liver failure and coagulation failure, or
  • liver failure and West Haven grade 3-4 hepatic encephalopathy.

Group 2

• ACLF 1 with renal failure (serum creatinine ≥ 2.0 and < 3.5 mg/dL), OR

• ACLF 2 with

  • liver failure and renal failure (serum creatinine ≥ 2.0 and < 3.5 mg/dL), or
  • coagulation failure and renal failure (serum creatinine ≥ 2.0 and < 3.5 mg/dL).

Inclusion Criteria:

1. Age 18 to 75 years, inclusive, at screening.

2. Stable diagnosis of AD, ACLF Grade 1 or ACLF Grade 2 for no less than 2 days (as determined at the discretion of the investigator)*.

3. Anticipated duration of hospital stay of at least 7 days.

4. For Group 1:

   • AD with SCr ≥ 1 and < 2 mg/dL, OR

   • ACLF 1 with

     • Tbil ≥ 12 mg/dL, SCr ≥ 1.5 and < 2 mg/dl, and HE 0-2, or
     • Tbil ≥ 12 mg/dL, and SCr < 1.5 mg/dL, and HE 1-2, or
     • INR ≥ 2.5, SCr ≥ 1.5 and < 2 mg/dl, and HE 0-2, or
     • INR ≥ 2.5, SCr < 1.5 mg/dL, and HE 1-2, OR

   • ACLF 2 with

     • Tbil ≥ 12 mg/dL, INR ≥ 2.5, and SCr < 2 mg/dL, or
     • Tbil ≥ 12 mg/dL, HE 3-4, and SCr < 2 mg/dL

5. For Group 2:

   • ACLF 1 with SCr ≥ 2.0 and < 3.5 mg/dL, OR

   • ACLF 2 with

     • Tbil ≥ 12 mg/dL, and SCr ≥ 2 and < 3.5 mg/dL, or
     • INR ≥ 2.5, and SCr ≥ 2 and < 3.5 mg/dL.

6. Female patients must be of non-childbearing potential, or, if non-sterile, must agree to sexual abstinence or use a highly effective method of contraception from Screening to 3 days after the final dose.

7. Non sterile male patients must agree to sexual abstinence or use a highly effective method of contraception from Screening to 3 days after the final dose if sexually active.

8. Able to comprehend and willing to sign an informed consent form, or, if unable to consent, consent is conducted per local requirements.

Exclusion Criteria:

1. Diagnosis of AD or ACLF (of any grade) >14 days before enrollment*.
2. Circulatory failure.
3. Respiratory failure i.e. PaO2/FiO2 ≤ 200 and/or baseline SpO2/FiO2 ≤ 214.
4. Brain failure (West Haven grade 3 or 4 hepatic encephalopathy) with coagulation failure (INR > 2.5).
5. Gastrointestinal bleeding within 72 hours prior to enrollment. (Subjects who fail this criterion may qualify after 72 hours).
6. Uncontrolled bacterial infection (urinary tract infection, spontaneous bacterial peritonitis, pneumonia, bacteremia, soft tissue infections, etc.) (as determined at the discretion of the investigator).
7. Invasive fungal infection.
8. Platelet count <30,000 cells/mL.
9. White blood cell count <1000 cells/uL.
10. Patients on hemodialysis or continuous venovenous hemofiltration.
11. Patients who have undergone or are scheduled for imminent organ transplantation. (Patients may be on a transplant list as long as no date has been set for transplantation)
12. Hospitalization for ACLF within the 3 months prior to screening.
13. History of hepatocellular carcinoma, unless within Milan Criteria (up to 3 lesions each < 3 cm or 1 lesion < 5 cm; no extrahepatic involvement; no evidence of gross vascular invasion).
14. Active non-hepatic malignancy.
15. Parkinson's disease, Parkinsonian-type symptoms (gait disorder, tremor, etc.), restless leg syndrome or other movement disorders other than asterixis.
16. Fulminant Wilson's, fulminant autoimmune hepatitis, or Budd-Chiari syndrome.
17. Septic shock (hypotension requiring vasopressors to maintain a mean arterial pressure of 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L (> 18 mg/dL) after adequate fluid resuscitation.
18. Patients who have undergone placement of a transjugular intrahepatic portosystemic shunt (TIPS) or surgical shunt in the past 6 months.
19. Any invasive procedure within 48 hours prior to enrollment with high risk of uncontrolled bleeding (as determined at the discretion of the investigator).
20. Female with a positive pregnancy test or lactating.
21. Positive results for human immunodeficiency virus HIV-1 or HIV-2.
22. Current treatment with trimetazidine.
23. Known allergy to trimetazidine or excipients.
24. Currently receiving an investigational treatment.
25. Any condition that, in the opinion of the Investigator (or designee), would limit the subject's ability to complete or participate in this clinical study.