Obeticholic Acid Treatment in Patients With Bile Acid Diarrhoea: an Open-label, Pilot Study of Mechanisms, Safety and Symptom Response.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 2
- 主要终点
- Changes in Fasting FGF19
研究概览
简要总结
The investigators propose to develop studies of obeticholic acid (OCA) in patients with bile acid diarrhoea. OCA is a semisynthetic bile acid, also known as 6αethylchenodeoxycholic acid or INT747,and is a potent farnesoid X receptor (FXR) agonist. Preliminary data suggests that patients with bile acid diarrhoea have impaired production of the ileal hormone Fibroblast Growth Factor 19 (FGF19). FGF19 is stimulated by FXR agonists, and regulates bile acid synthesis. This study is a pilot, proof-of-concept, open-label study to investigate whether OCA can stimulate FGF19 in bile acid diarrhoea patients to provide a safe and effective treatment.
详细描述
Bile acid diarrhoea (BAD) is an under-recognised but common condition of chronic watery diarrhoea. BAD may be secondary to ileal disease affecting the reabsorption and the enterohepatic circulation of bile acids (bile acid malabsorption) or can be an idiopathic, primary BAD (PBAD). In work published in 2009, we described a new mechanism to explain this syndrome of primary BAD.
Blood levels of the hormone fibroblast growth factor 19 (FGF19) are reduced in primary and secondary BAD, producing impaired feedback inhibition of bile acid synthesis, leading to excess faecal bile acids, which then produce diarrhoea by stimulating colonic secretion. FGF19 is synthesised in the ileum and we have shown transcription is markedly induced by farnesoid X receptor(FXR) agonists such as chenodeoxycholic acid, an abundant natural bile acid. More potent FXR agonists are logical diagnostic and therapeutic agents for this condition, and obeticholic acid (OCA), which is 100x more potent than chenodeoxycholic acid, has recently been developed. It has been used in phase II studies in primary biliary cirrhosis and in non-alcoholic steatohepatitis where a relatively common side-effect was constipation.
We aim to investigate the effects of OCA in patients with primary and secondary BAD to determine whether FGF19 is able to be stimulated in these conditions. We will compare these responses to those in control patients with chronic diarrhoea but without evidence of BAD. It is possible in BAD that the defect in FGF19 levels is due to an inability to respond to FXR stimulation (particularly likely in secondary BAD after ileal resection). Patients with primary BAD may be able to respond and benefit from an increase in FGF19 levels.
This study aims to obtain pilot data on the effects of OCA on FGF19, other markers of bile acid metabolism and patient symptoms including diarrhoea. These are early phase II, proof of concept studies.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Primary BAD
Defined as SeHCAT <10% without other causes such as Crohn's disease and/or ileal resection
干预措施: Obeticholic acid (Drug)
Secondary BAD
With Crohn's disease or ileal resection
干预措施: Obeticholic acid (Drug)
Idiopathic Diarrhoea Controls
Chronic diarrhoea with SeHCAT >15% and no Crohn's or ileal resection
干预措施: Obeticholic acid (Drug)
结局指标
主要结局
Changes in Fasting FGF19
时间窗: Day 0, Day 15
The primary outcome measure is the change over 2 weeks in fasting serum fibroblast growth factor (FGF19) in 3 groups of patients: primary bile acid diarrhoea, secondary bile acid diarrhoea, and a control population of patients with chronic diarrhoea but with normal bile acid retention.
次要结局
- Changes in Non-fasting Response of FGF19 to OCA(Day 0, Day 15)
- Changes in Serum Total Bile Acids.(Day 0, Day 15)
- Changes in Fasting 7α-hydroxy-4-cholesten-3-one(Day 0, Day 15)
- Changes in Mean Stool Form(Week 2, Week 4)
- Changes in Stool Frequency(Week 2, Week 4)
- Change in Stool Index(Week 2, Week 4)