Peroxisome Proliferator-Activated Receptor Agonists to Prevent Primary Sclerosing Cholangitis Recurrence After Liver Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Mayo Clinic
- 入组人数
- 80
- 试验地点
- 2
- 主要终点
- To determine the incidence of rPSC in LT recipients treated with fenofibrate, compared with an untreated control cohort.
研究概览
简要总结
This study aims to determine the efficacy of 36 months once-daily fenofibrate in preventing clinically-detectable recurrence of primary sclerosing cholangitis after liver transplantation, compared with a historical control cohort that was not treated with
详细描述
Primary sclerosing cholangitis (PSC), an immune-mediated, progressive cholestatic disease with no well-established pharmacologic treatment, has an annual incidence of 2.0 per 100,000 and is responsible for 5% of liver transplants (LT) performed in the United States. Recurrent PSC (rPSC) after LT occurs in 8-27% at 5 years and is associated with an over 40% risk of graft loss.
Because PSC patients undergo LT at a younger age than non-PSC patients (median 40-50 years vs 60 years for most other LT indications), rPSC poses significant lifetime morbidity and mortality risk, and development of its early signs of biliary injury, particularly the development cholestasis (elevated alkaline phosphatase), is routinely monitored in the post-transplant setting.
There is no established pharmacologic treatment for rPSC, and the disease is usually characterized by progressive cholestasis to biliary stricturing, cholangitis, allograft fibrosis and ultimately liver failure. Trials of ursodeoxycholic acid and oral vancomycin have been inconclusive. Since most transplants for PSC are performed with Roux-en-Y biliary reconstructions that make re-transplantation challenging, any pharmacologic intervention to reduce the risk of rPSC would represent a breakthrough in disease management.
Cholestasis appears to be a surrogate for PSC disease progression since improvement in alkaline phosphatase levels is associated with slower disease progression, lower rates of cholangiocarcinoma, and improved survival in the pre-transplant setting. Peroxisome proliferator-activated receptor (PPAR) agonists (e.g. fenofibrate, bezafibrate, seladelpar, elafibranor) reduce bile acid-mediated biliary injury by downregulating their synthesis and activity, and promoting choleresis. PPAR agonists have demonstrated efficacy in potently improving cholestasis in PSC pre-transplant, and other cholestatic liver diseases post-transplant.
While fibrates have been shown to improve both biochemical and clinical parameters of PSC in non-transplant patients, whether they can prevent clinically detectable rPSC after transplantation has not been studied. Extrapolating the pre-transplant data to the post-transplant setting, this study hypothesizes that mitigating cholestasis with the use of fibrates in transplant recipients may impede the development of rPSC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults aged 18-75 irrespective of gender who have undergone LT for PSC or PSC-related liver malignancy between 1 year and 7 years (inclusive) prior to study enrollment
- •Absence of rPSC at time of study enrollment
- •At least one of the following additional features that increase risk of rPSC
- •LT performed for cholangiocarcinoma
- •Concurrent inflammatory bowel disease
- •Any episode of cytomegalovirus viremia in the post-transplant period before study enrollment
- •Any episode of acute cellular rejection in the post-transplant period before the study enrollment
- •If target enrollment of 40 patients is not achieved during the first 6 months of study, we will remove f(iii) inclusion criteria to expand enrollment to any patient meeting the other inclusion/
排除标准
- •Due to lab requirements, we will only enrol patients who are within a 3 hour driving distance of Mayo Clinic Arizona and/or are willing to travel to Mayo Clinic Arizona at 4 month intervals during the study at own cost.
- •Exclusion criteria:
- •Presence of ischemic cholangiopathy which can mimic rPSC
- •LT performed for primary biliary cholangitis or autoimmune hepatitis, or PSC with overlapping primary biliary cholangitis or autoimmune hepatitis, which may recur after LT and confound assessment of cholestasis
- •Unaddressed post-LT hepatic artery compromise (e.g thrombosis, stenosis) which can mimic rPSC
- •History of total colectomy for curative treatment of ulcerative colitis which reduces risk of rPSC
- •Baseline GFR <30 ml/min which precludes administration of fenofibrate
- •Previously known intolerance or allergy to fenofibrate
- •Other clinically significant comorbid condition, including inability to provide consent and psychiatric conditions, which in the opinion of the study team, may interfere with patient treatment, safety, assessment, or compliance with the treatment
- •Female participants that are pregnant or planning to become pregnant
研究组 & 干预措施
Treatment
Individuals who underwent liver transplantation for primary sclerosing cholangitis 1-7 years before study initiation, and meeting study criteria, will receive fenofibrate 160mg oral daily for 36 months
Participants will undergo the following serum assessments as part of the study every 3 months during the study period: total bile acids, bile acid profile, fibroblast growth factor 19, and 7-alpha-C4
Participants will undergo gadoxate-enhanced magnetic resonance imaging at baseline, 12 months, and 36 months.
干预措施: Fenofibrate (drug) (Drug)
Treatment
Individuals who underwent liver transplantation for primary sclerosing cholangitis 1-7 years before study initiation, and meeting study criteria, will receive fenofibrate 160mg oral daily for 36 months
Participants will undergo the following serum assessments as part of the study every 3 months during the study period: total bile acids, bile acid profile, fibroblast growth factor 19, and 7-alpha-C4
Participants will undergo gadoxate-enhanced magnetic resonance imaging at baseline, 12 months, and 36 months.
干预措施: Blood draw for the laboratory assessment (Diagnostic Test)
Treatment
Individuals who underwent liver transplantation for primary sclerosing cholangitis 1-7 years before study initiation, and meeting study criteria, will receive fenofibrate 160mg oral daily for 36 months
Participants will undergo the following serum assessments as part of the study every 3 months during the study period: total bile acids, bile acid profile, fibroblast growth factor 19, and 7-alpha-C4
Participants will undergo gadoxate-enhanced magnetic resonance imaging at baseline, 12 months, and 36 months.
干预措施: MRI using a hepatobiliary phase contrast agent (Gd-EOB-DPTA) (Diagnostic Test)
结局指标
主要结局
To determine the incidence of rPSC in LT recipients treated with fenofibrate, compared with an untreated control cohort.
时间窗: 36 months
Proportion of recipients transplanted for PSC who develop rPSC during a 36-month fenofibrate treatment period, compared to the rate of rPSC in a untreated cohort. The diagnosis of rPSC will be made based on established diagnostic criteria (see Study Design)
次要结局
- To quantify the associations between serum alkaline phosphatase and rPSC development in LT recipients treated with fenofibrate(36 months)
- To quantify the associations between total serum bile acid level and rPSC development in LT recipients treated with fenofibrate(36 months)
- To quantify the associations between serum bile acid profile and rPSC development in LT recipients treated with fenofibrate(36 months)
- To quantify the associations between fibroblast growth factor 19 level and rPSC development in LT recipients treated with fenofibrate(36 months)
- To quantify the associations between serum 7-alpha-hydroxy-4-cholesten-3-one level and rPSC development in LT recipients treated with fenofibrate(36 months)
- To quantify the association between quantitative biliary flow dynamics demonstrated by gadoxetate-enhanced and T1 mapping magnetic resonance imaging with rPSC development in LT recipients treated with fenofibrate(36 months)
研究者
Channa R Jayasekera, MD, MSc
Principal Investigator
Mayo Clinic