Clinical trial NCT03737448: TRimetazidine for acUte on Chronic Liver Failure STudy
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
Overall status: SUSPENDED
Phase: PHASE1
Conditions: Acute-On-Chronic Liver Failure
Lead sponsor: Martin Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2018-11-09
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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).

Eligibility criteria: 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.

Primary outcomes:
measure: plasma pharmacokinetics
timeFrame: 28 days
measure: plasma pharmacokinetics
timeFrame: 28 days
Secondary outcomes:
measure: Incidence of treatment-emergent adverse events [Safety and Tolerability]
timeFrame: 90 days
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University of Graz
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Antwerp
country: Belgium
facility: University of Antwerp
city: Brussels
country: Belgium
facility: Erasme Hospital
city: Lille
country: France
facility: Hospital Claude Huriez
city: Paris
country: France
facility: Hospital Pitie-Salpetriere
city: Rennes
country: France
facility: Rennes University Hospital
city: Villejuif
country: France
facility: Hôpital Paul Brousse
city: Essen
country: Germany
facility: University of Essen
city: Frankfurt
country: Germany
facility: JW Goethe Clinic
city: Halle
country: Germany
facility: Universitätsklinikum Halle Klinik und Poliklinik für Innere Medizin I
city: Hannover
country: Germany
facility: University of Hannover
city: Heidelberg
country: Germany
facility: University of Heidelberg
city: Leipzig
country: Germany
facility: University of Leipzig
city: Münster
country: Germany
facility: University of Münster
city: Barcelona
country: Spain
facility: Hospital Clinic
city: Barcelona
country: Spain
facility: Hospital Valle de Hebron
city: Córdoba
country: Spain
facility: Hospital Reina Sofia
city: Madrid
country: Spain
facility: Hospital Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Puerta de Hierro
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Santander
country: Spain
facility: Hospital Marques de Valdecilla Santander
city: Seville
country: Spain
facility: Hospital Virgen del Rocio
Study officials:
affiliation: Martin Pharmaceuticals
name: Chief Medical Officer
role: STUDY_DIRECTOR
References: