A Phase I/II, Randomized, Double-Blind Intervention Trial for Evaluating the Safety and Efficacy of Imatinib in Subjects With Advance Fibrosis
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Assessment of liver fibrosis score changes from baseline to 6 months
研究概览
简要总结
When a recurrent, long-term injury and inflammation of the liver causes an excessive accumulation of damaged tissue, a dangerous condition called liver fibrosis develops. Most chronic liver diseases eventually lead to fibrosis. Activated hepatic stellate cells (aHSC) play an important role in the development of hepatic fibrosis. Inhibiting the proliferation of stellate cells and preventing their differentiation and activation is an ideal strategy for ameliorating hepatic fibrosis. Hence imatinib have been prescribed as a promising drug to limit the progression of liver fibrosis as a clinical inhibitor of tyrosine kinase which can affect the two main pathways leading to hepatic stellate cells activation.
详细描述
Liver fibrosis can be categorized as a serious health problem worldwide. It is widely recognized that activated hepatic stellate cells (HSC) play a pivotal role in pathological development of liver fibrosis. The activated hepatic stellate cells (aHSCs) are main producers of ECM, which play a significant role in scarring process of the liver derived from variety of etiologies, such as hepatitis B or C virus infection, chronic alcohol abuse, non-alcoholic steatohepatitis, cholestasis, and autoimmune hepatitis. Due to lack of effective treatments, chronic liver diseases and liver fibrosis can eventually progress to liver cirrhosis and even liver cancer. Inhibition of the stellate cell proliferation, differentiation and prevention of its activation is appealing as an ideal strategy for ameliorating hepatic fibrosis. A platelet-derived growth factor (PDGF) is the most potent proliferating stimulus for HSC. Imatinib mesylate (Gleevec), a clinically used PDGF receptor (PDGFR) tyrosine kinase inhibitor could be a promising molecular targeted approach to limit the liver fibrosis development. IL-6/STAT3 is one the pivotal signaling pathways for the activation of HSCs. Herein in our previous study we found that Imatinib upregulates miR-124 and interferes simultaneously with STAT3-HLF-IL-6 pathway. However, due to effective role of imatinib in blocking two important liver fibrosis related pathways, pharmacokinetics of imatinib in patients with liver fibrosis have never been assessed. This study is a phase I/II, double blind labeled, randomized, double arms clinical trial. Consequently, this phase I/II trial was initiated to evaluate the safety and efficacy of imatinib in patients with advanced liver fibrosis. 20 patients with clinical and/or pathologic diagnosis of liver fibrosis grade 3-4 will be registered at Taleghani hospital (Tehran). 10 patients will receive standard medication and imatinib for 24 weeks at the dose of 200mg/day orally. Another 10 patients will be treated with standard medication of liver fibrosis and placebo of imatinib drug as a control group.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
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
- •Males or females between18-75 years old with a clinically confirmed diagnosis of Fibrosis with grade 3-4 by Metavir score.
- •Negative alcohol screen
- •Able to understand and willing to voluntarily sign an informed consent form (ICF) and Health Insurance Portability and Accountability Act (HIPAA) authorization.
排除标准
- •Known cardiovascular disease.
- •Requiring any of the following medications during the duration of the study:History of cirrhosis based on imaging or clinical criteria and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding.
- •History of hepatocellular carcinoma (HCC)
- •History of malignancy within the past 5 years or ongoing malignancy other than basal cell carcinoma, or resected noninvasive cutaneous squamous carcinoma at the time of Screening visit.
- •Active, serious infections that requires parenteral antibiotic or antifungal therapy within 30 days prior to Screening visit.
- •Females who are pregnant or breastfeeding.
- •Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents and immunomodulating agents (such as systemic corticosteroids, interleukins, interferons).
- •Use of any experimental medications within the last 6 months of Screening Visit.
- •Familial dyslipidemia Weight loss of >5% within 6 months prior to Screening, based on subject's reporting Currently or participated in a weight loss program within the last 6 months.
- •Any history of bariatric surgery Diabetes mellitus Type I.
- •Daily alcohol intake >20 ml (2 units)/day for women and 30 ml (3 units)/day for men (on average), as per Alcohol Use Disorders Identification Test (AUDIT) questionnaire at Screening and plan to consume the same alcohol amount referenced above during the trial.
- •Use of any immunosuppressive medication, anti-inflammatory monoclonal antibody treatment, or chronic systemic corticosteroids >10 mg prednisone-equivalent concurrently or within 1 year prior to Screening.
- •Uncontrolled or clinically unstable thyroid disease, in the judgment of the Principal Investigator.
- •History or presence of hepatitis B or C or human immunodeficiency virus (HIV) Uncontrolled arterial hypertension.
- •Any severe, acute, or chronic medical or psychiatric condition that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or in compliance with the requirements of the study, or may interfere with the interpretation of study results and, in the investigator's opinion, would make the subject inappropriate for entry into this study.
- •Subjects who have previously received imatinib or who have history of hypersensitivity, allergy, intolerance or contraindication to imatinib.
研究组 & 干预措施
Imatinib Drug
Standard medication of liver fibrosis + Imatinib 200 mg 1 time a day.
干预措施: Imatinib 200mg (Drug)
Placebo
Standard medication of liver fibrosis + placebo as a control group.
干预措施: Placebo (Drug)
结局指标
主要结局
Assessment of liver fibrosis score changes from baseline to 6 months
时间窗: 6 months
by the FibroScan system
次要结局
- Albumin levels changes in baseline, 3 months and 6months(every 3 months for 6 months)
- Blood sugar changes in baseline, 3 months and 6months(every 3 months for 6 months)
- Alanine aminotransferase serum levels changes in baseline, 3 months and 6months(every 3 months for 6 months)
- Aspartate aminotransferase serum levels changes in baseline, 3 months and 6months(every 3 months for 6 months)
- Bilirubin levels changes in baseline, 3 months and 6months(every 3 months for 6 months)
- Detecting changes of Interleukin-6 from baseline to 6 months(6 months)
- Detecting changes of Tumor necrosis factor (TNF)-alpha from baseline to 6 months(6 months)
- Fasting insulin changes in baseline, 3 months and 6months(every 3 months for 6 months)
- Complete blood count changes in baseline, 3 months and 6months(every 3 months for 6 months)
- International normalized ratio (INR) changes in baseline, 3 months and 6months(every 3 months for 6 months)
- Prothrombin time (PT) changes in baseline, 3 months and 6months(every 3 months for 6 months)