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TRimetazidine for acUte on Chronic Liver Failure STudy (TRUST)

Primary Purpose

Acute-On-Chronic Liver Failure

Status
Suspended
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Trimetazidine
Sponsored by
Martin Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Acute-On-Chronic Liver Failure

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Medical University of Graz
  • Medical University of Innsbruck
  • Medical University of Vienna
  • University of Antwerp
  • Erasme Hospital
  • Hospital Claude Huriez
  • Hospital Pitie-Salpetriere
  • Rennes University Hospital
  • Hôpital Paul Brousse
  • University of Essen
  • JW Goethe Clinic
  • Universitätsklinikum Halle Klinik und Poliklinik für Innere Medizin I
  • University of Hannover
  • University of Heidelberg
  • University of Leipzig
  • University of Münster
  • Hospital Clinic
  • Hospital Valle de Hebron
  • Hospital Reina Sofia
  • Hospital Gregorio Marañón
  • Hospital Puerta de Hierro
  • Hospital Ramon y Cajal
  • Hospital Marques de Valdecilla Santander
  • Hospital Virgen del Rocio

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group 1

Group 2

Arm Description

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.

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).

Outcomes

Primary Outcome Measures

plasma pharmacokinetics
Cmax
plasma pharmacokinetics
AUC

Secondary Outcome Measures

Incidence of treatment-emergent adverse events [Safety and Tolerability]
Adverse events

Full Information

First Posted
November 7, 2018
Last Updated
March 2, 2021
Sponsor
Martin Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT03737448
Brief Title
TRimetazidine for acUte on Chronic Liver Failure STudy
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Suspended
Why Stopped
Lack of enrollment
Study Start Date
November 28, 2018 (Actual)
Primary Completion Date
June 30, 2021 (Anticipated)
Study Completion Date
June 30, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Martin Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute-On-Chronic Liver Failure

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Group 2
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Trimetazidine
Intervention Description
Subjects with receive up to 60 mg daily
Primary Outcome Measure Information:
Title
plasma pharmacokinetics
Description
Cmax
Time Frame
28 days
Title
plasma pharmacokinetics
Description
AUC
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Incidence of treatment-emergent adverse events [Safety and Tolerability]
Description
Adverse events
Time Frame
90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18 to 75 years, inclusive, at screening. 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)*. Anticipated duration of hospital stay of at least 7 days. 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 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. 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. 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. Able to comprehend and willing to sign an informed consent form, or, if unable to consent, consent is conducted per local requirements. Exclusion Criteria: Diagnosis of AD or ACLF (of any grade) >14 days before enrollment*. Circulatory failure. Respiratory failure i.e. PaO2/FiO2 ≤ 200 and/or baseline SpO2/FiO2 ≤ 214. Brain failure (West Haven grade 3 or 4 hepatic encephalopathy) with coagulation failure (INR > 2.5). Gastrointestinal bleeding within 72 hours prior to enrollment. (Subjects who fail this criterion may qualify after 72 hours). Uncontrolled bacterial infection (urinary tract infection, spontaneous bacterial peritonitis, pneumonia, bacteremia, soft tissue infections, etc.) (as determined at the discretion of the investigator). Invasive fungal infection. Platelet count <30,000 cells/mL. White blood cell count <1000 cells/uL. Patients on hemodialysis or continuous venovenous hemofiltration. 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) Hospitalization for ACLF within the 3 months prior to screening. 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). Active non-hepatic malignancy. Parkinson's disease, Parkinsonian-type symptoms (gait disorder, tremor, etc.), restless leg syndrome or other movement disorders other than asterixis. Fulminant Wilson's, fulminant autoimmune hepatitis, or Budd-Chiari syndrome. 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. Patients who have undergone placement of a transjugular intrahepatic portosystemic shunt (TIPS) or surgical shunt in the past 6 months. Any invasive procedure within 48 hours prior to enrollment with high risk of uncontrolled bleeding (as determined at the discretion of the investigator). Female with a positive pregnancy test or lactating. Positive results for human immunodeficiency virus HIV-1 or HIV-2. Current treatment with trimetazidine. Known allergy to trimetazidine or excipients. Currently receiving an investigational treatment. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chief Medical Officer
Organizational Affiliation
Martin Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Medical University of Graz
City
Graz
Country
Austria
Facility Name
Medical University of Innsbruck
City
Innsbruck
Country
Austria
Facility Name
Medical University of Vienna
City
Vienna
Country
Austria
Facility Name
University of Antwerp
City
Antwerp
Country
Belgium
Facility Name
Erasme Hospital
City
Brussels
Country
Belgium
Facility Name
Hospital Claude Huriez
City
Lille
Country
France
Facility Name
Hospital Pitie-Salpetriere
City
Paris
Country
France
Facility Name
Rennes University Hospital
City
Rennes
Country
France
Facility Name
Hôpital Paul Brousse
City
Villejuif
Country
France
Facility Name
University of Essen
City
Essen
Country
Germany
Facility Name
JW Goethe Clinic
City
Frankfurt
Country
Germany
Facility Name
Universitätsklinikum Halle Klinik und Poliklinik für Innere Medizin I
City
Halle
Country
Germany
Facility Name
University of Hannover
City
Hannover
Country
Germany
Facility Name
University of Heidelberg
City
Heidelberg
Country
Germany
Facility Name
University of Leipzig
City
Leipzig
Country
Germany
Facility Name
University of Münster
City
Münster
Country
Germany
Facility Name
Hospital Clinic
City
Barcelona
Country
Spain
Facility Name
Hospital Valle de Hebron
City
Barcelona
Country
Spain
Facility Name
Hospital Reina Sofia
City
Córdoba
Country
Spain
Facility Name
Hospital Gregorio Marañón
City
Madrid
Country
Spain
Facility Name
Hospital Puerta de Hierro
City
Madrid
Country
Spain
Facility Name
Hospital Ramon y Cajal
City
Madrid
Country
Spain
Facility Name
Hospital Marques de Valdecilla Santander
City
Santander
Country
Spain
Facility Name
Hospital Virgen del Rocio
City
Seville
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No

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TRimetazidine for acUte on Chronic Liver Failure STudy

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