A Phase 1b Open-Label Study Assessing the Pharmacokinetics, Tolerability, and Safety of Oral Trimetazidine in Subjects With Acute-on-Chronic Liver Failure
试验速览
- 阶段
- 1 期
- 状态
- 暂停
- 发起方
- 入组人数
- 30
- 试验地点
- 24
- 主要终点
- plasma pharmacokinetics
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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 ≤
- •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-
- •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.
研究组 & 干预措施
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.
干预措施: Trimetazidine (Drug)
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).
干预措施: Trimetazidine (Drug)
结局指标
主要结局
plasma pharmacokinetics
时间窗: 28 days
AUC
次要结局
- Incidence of treatment-emergent adverse events [Safety and Tolerability](90 days)