TRimetazidine for acUte on Chronic Liver Failure STudy

Acute-On-Chronic Liver Failure Clinical Trial

— TRUST  

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT03737448
• Other study ID #: MP-0614-001
• Status: Suspended
• Phase: Phase 1
• Start date: November 28, 2018
• Est. completion date: June 30, 2021

Study information

• Verified date: March 2021
• Source: Martin Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 30
• Est. completion date: June 30, 2021
• Est. primary completion date: June 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute-On-Chronic Liver Failure
• End Stage Liver Disease
• Hepatic Insufficiency
• Liver Failure

Intervention

Drug:
• Trimetazidine
Subjects with receive up to 60 mg daily

Locations

Country	Name	City	State
Austria	Medical University of Graz	Graz
Austria	Medical University of Innsbruck	Innsbruck
Austria	Medical University of Vienna	Vienna
Belgium	University of Antwerp	Antwerp
Belgium	Erasme Hospital	Brussels
France	Hospital Claude Huriez	Lille
France	Hospital Pitie-Salpetriere	Paris
France	Rennes University Hospital	Rennes
France	Hôpital Paul Brousse	Villejuif
Germany	University of Essen	Essen
Germany	JW Goethe Clinic	Frankfurt
Germany	Universitätsklinikum Halle Klinik und Poliklinik für Innere Medizin I	Halle
Germany	University of Hannover	Hannover
Germany	University of Heidelberg	Heidelberg
Germany	University of Leipzig	Leipzig
Germany	University of Münster	Münster
Spain	Hospital Clinic	Barcelona
Spain	Hospital Valle de Hebron	Barcelona
Spain	Hospital Reina Sofia	Córdoba
Spain	Hospital Gregorio Marañón	Madrid
Spain	Hospital Puerta de Hierro	Madrid
Spain	Hospital Ramon y Cajal	Madrid
Spain	Hospital Marques de Valdecilla Santander	Santander
Spain	Hospital Virgen del Rocio	Seville

Sponsors (1)

Lead Sponsor	Collaborator
Martin Pharmaceuticals

Countries where clinical trial is conducted

Austria,  Belgium,  France,  Germany,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	plasma pharmacokinetics	Cmax	28 days
Primary	plasma pharmacokinetics	AUC	28 days
Secondary	Incidence of treatment-emergent adverse events [Safety and Tolerability]	Adverse events	90 days