对熊去氧胆酸应答不充分的原发性胆汁性肝硬化患者应用奥贝胆酸有效

来源:  作者:
背景与目的:通过随机对照研究评估对熊去氧胆酸应答不充分的原发性胆汁性肝硬化(PBC)患者应用奥贝胆酸(OCA)的有效性和安全性。
 
方法:进行一项双盲试验,对确诊PBC的患者给予至少6个月的标准剂量熊去氧胆酸治疗,并筛选应答不充分患者,其中165例(95%女性)患者入选,碱性磷酸酶(ALP)均高于正常值上线的1.5~10倍。将患者随机分为OCA 10、25、50 mg剂量组及安慰剂组,1次/d,持续3个月。研究全程,患者仍维持原熊去氧胆酸剂量。初级研究终点为ALP水平从基线(第0天)到实验结束(第85天或提前结束)的改变,次级研究终点为评估意向性治疗患者肝酶、胆红素、白蛋白等较基线水平的改变。同时进行一项开放标签延伸研究,78例患者入选,其中61例患者完成第1年研究。
 
结果:OCA在获得初级研究终点方面优于安慰剂组,给予OCA的受试者ALP平均水平从基线到研究结束的相对降低率对比安慰组,差异有统计学意义(P<0.0001,所有OCA组vs安慰剂组)。OCA组ALP水平较基线平均下降21%~25%,安慰剂组下降3%。OCA组69%(68/99)的患者ALP水平至少下降20%,较安慰组的8%(3/37),差异有统计学意义(P<0.0003)。OCA组γ-谷氨酰转肽酶(GGT)水平平均下降48%~63%,安慰剂组下降7%。OCA组谷丙转氨酶(ALT)水平平均下降21%~35%,安慰剂组无ALT下降。皮肤瘙痒是主要的不良事件,安慰剂组发生率为50%,OCA 10、25、50 mg组发生率分别为47%(P>0.05)、87%(P<0.0003)、80%(P<0.006)。在延伸研究中,ALP水平持续下降,1年后由基线水平的(285±15) U/L降至(202±11) U/L。
 
结论:对熊去氧胆酸应答不充分的PBC患者,每日口服OCA 10~50 mg,与安慰剂组相比可显著降低ALP、γ-GGT、ALT水平,皮肤瘙痒的发生率和严重程度在10 mg组最低。在开放标签延伸研究中,患者对OCA的生物化学反应持续至12个月。
  
文献来源:Gastroenterology. 2015 Apri;148(4):751-761.
(译:薛倩,王晶桐)
北京大学人民医院消化内科
 
原文链接:http://www.sciencedirect.com/science/article/pii/S0016508514015303#

Efficacy of Obeticholic Acid in Patients With Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid
 
Background & Aims: We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy.
 
Methods: We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year.
 
Results: OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P<0.0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P<0.0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P<0.0003), and 80% (P<0.006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of (202±11) U/L after 12 months vs (285±15) U/L at baseline.
 
Conclusions: Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial.

From:Gastroenterology. 2015 Apri;148(4):751-761.
 
[Original connection]
http://www.sciencedirect.com/science/article/pii/S0016508514015303#

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