Pirfenidone in Combination With Standard of Care Treatment in Patients With Advanced Liver Fibrosis. Multicenter, Open Trial Focused on Safety, Fibrosis Efficacy Evaluation, and Pharmacokinetic Data.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 122
- 试验地点
- 1
- 主要终点
- Safety endpoint based on clinical side effects
研究概览
简要总结
Pirfenidone (PFD), an oral antifibrotic drug with anti-inflammatory and anti-oxidant properties, has been granted marketing authorization by the European Medicine Agency and FDA, for the treatment of idiopathic pulmonary fibrosis (IPF). However, few studies have focused on its clinical utilization in patients with advanced hepatic fibrosis. Therefore, Investigators aim to evaluate a prolonged-release PFD formulation (PR-PFD) plus standard of care management on disease progression in patients with advanced liver fibrosis (ALF).
Methods: Patients with diverse chronic liver disease etiology (alcohol-related, hepatitis B or C, autoimmune or fatty liver disease) will be screened with two non invasive liver fibrosis methods (Fibroscan®) and Fibro Test®) and those with ALF (F3 or F4) will be treated for at least 12 months with PR-PFD. Antifibrotic effects Will be assessed at 6 and 12 months; variations greater than 30% in estimated fibrosis scores or 1 point on the METAVIR scale will be considered clinically significant. PFD plasma levels, serum endothelin-1, IL6, TNFα and TGFβ1, Quality of life and fatigue scales will be evaluated. Parametric and non parametric statistics will be utilized and p values lower tan 5% will be considered clinically significant.
详细描述
The study will be conducted in compliance with International Standard good clinical practices (GCPs) and the Declaration of Helsinki. The protocol was approved by local Institutional Review Board and registered in clinical trials.gov.
Clinical and Laboratory Evaluation Blood counts and liver function tests (bilirubin, albumin, prothrombin time expressed as international normalized ratio (INR), serum transaminases, glucose, and creatinine) are measured at 12-week intervals. Patient's somatometric measurements (height and body weight), vital signs, and frequency of adverse events (AE) are recorded. Liver enzymes will be scored as stable, improving, or worsening.
Study End Points The primary efficacy endpoint is a reduction of fibrosis score by at least 30% either in Fibro Test units or kilo Pascals (kPa) according to hepatic elastography or a reduction of 1 point on the METAVIR scale. Secondary efficacy endpoints include improvement in alanine aminotranferase (ALT) and/or aspartate aminotransferase (AST), albumin, serum concentrations of TGFbeta, IL-1 and IL-6 and endothelin, and Child-Pugh and MELD scores. Worsening MELD is defined as switching from a lower-score to a higher-score and improving as switching from a higher-score to a lower-score, where Group 1 was MELD ≤ 9, Group 2 10-19, and Group 3 > 20.
Primary safety endpoints include clinical side effects, blood profile abnormalities, overall survival, and pharmacokinetic (PK) findings. Secondary safety endpoints included quality of life scores.
Evaluation and Classification of Fibrosis Outcomes Fibrosis-regression profile (FRP): decreases >30% in FT score or 30% in kPa in liver stiffness measurement (LSM) or decreasing 1 point on the METAVIR score comparing baseline and M12 measurements.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with chronic liver disease whose fibrosis continued to progress despite abstaining from alcohol (ALD), achieving sustained virologic response (VHC), or otherwise maintaining stable disease (NAFLD, AIH)..
- •Advanced liver fibrosis defined as fibrosis grade 3 or grade 4 according to METAVIR scale based in two non-invasive liver fibrosis evaluation methods (FibroScan and Fibrotest).
- •Stable liver disease.
排除标准
- •Patients with mild fibrosis (F1-F2)
- •Under medication with colchicine, silymarin, non-steroidal anti-inflammatory drugs, and any hepatotoxic drug.
- •Decompensation based on a history of hepatic encephalopathy, esophageal variceal bleeding, or ascites in the previous 6 months
- •HIV, Hepatitis B virus (HBV) or any active infectious processes not of a self-limited nature.
- •Concomitant or prior history of malignancy other than curatively-treated skin cancer or surgically-cured in situ carcinoma of the cervix.
- •Hemoglobinopathy or any disease associated with hemolysis.
- •History of significant cardiac or pulmonary disease that could be exacerbated by anemia.
- •Liver masses detected by baseline scanner or Alpha-fetoprotein >100 ng/L.
- •Alcohol or intravenous drug abuse within the previous year.
研究组 & 干预措施
Antifibrotic plus standard of care treatment
Prolonged release pirfenidone formulation in combination with standard of care treatment.
干预措施: Pirfenidone (Drug)
Antifibrotic plus standard of care treatment
Prolonged release pirfenidone formulation in combination with standard of care treatment.
干预措施: Standard of care (Other)
结局指标
主要结局
Safety endpoint based on clinical side effects
时间窗: 12 months
Clinical side effects wiil be evaluated according to World Health Organization grade modified toxicity scale.
Fibrosis reversal based on METAVIR
时间窗: 12 months
Reduction of fibrosis score by at least one point on the METAVIR fibrosis scale.
Fibrosis reversal based on Fibrotest
时间窗: 12 months
Reduction of fibrosis score by at least 30% in Fibrotest units.
Fibrosis reversal based on Hepatic Elastography
时间窗: 12 months
Reduction of fibrosis score by at least 30% in kilo Pascals (kPa) according to accurate hepatic elastography measurements.
次要结局
- Improvement in Quality of life(12 months)
- Improvement in Liver function values: bilirubin(12 months)
- Improvement in Liver function values:albumin(12 months)
- Improvement in fibrosis molecular marker(12 months)
研究者
Jorge L Poo
Principal Investigador, Head of Liver Clinic
Grupo Mexicano para el Estudios de las Enfermedades Hepaticas