肝性脑病的新型发作快速起作用 研究发现，降低氨水平比标

StephenW

Novel Tx for Hepatic Encephalopathy Works Fast
Lowers ammonia level more quickly than standard care, study finds

       by Joyce Frieden, News Editor, MedPage Today
    October 22, 2017

    This article is a collaboration between MedPage Today® and: Medpage Today

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    Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

WASHINGTON -- A new treatment for hepatic encephalopathy worked faster than usual care to reduce patients' ammonia levels, researchers said here.

In patients diagnosed with confirmed hyperammonemia at baseline, the new treatment, ornithine phenylacetate (OCR-002), lowered ammonia levels faster and led to faster clinical improvement compared with placebo, with a 21-hour median reduction in time to improvement (P=0.034), reported Robert Rahimi, MD, of the Baylor University Medical Center in Dallas, and colleagues in a poster presentation at at the Liver Meeting, the annual conference of the American Association for the Study of Liver Diseases.

OCR-002 "effectively binds ammonia, which we think is one of the very important curative mechanisms in hepatic encephalopathy," Stanley Bukofzer, MD, study co-author and chief medical officer at Ocera Therapeutics, which sponsored the trial, told MedPage Today in an interview. "If you can reduce the ammonia exposure in these patients, you can save the patients, get them over whatever caused the acute exacerbation ... and get them out of the hospital and back into some more normal functioning."

Time is of the essence in this disorder, he added. "The longer you leave [this problem], the more risk these patients are at ... You want to treat the patients as early and quickly as possible, and [OCR-002] seems to get the ammonia down very quickly."

Hepatic encephalopathy is a serious complication of cirrhosis, accounting for about 400,000 hospital admissions each year. Overall, about 15% of patients who experience this event will die from it, "so it's a very high-risk group of patients," Bukofzer said. Although rifaximin is commonly used for prophylaxis, it is not indicated for acute encephalopathy in hospitalized patients.

The researchers wanted to know whether OCR-002, which uses a novel scavenger mechanism to lower ammonia levels, would be helpful in these patients. They randomized 231 patients with cirrhosis and an acute episode of hepatic encephalopathy stages 2, 3, or 4 to either OCR-002 or placebo. The dose of the drug -- determined by the degree of liver failure -- was either 10, 15, or 20 g, infused intravenously daily for 5 days.

The treatment groups were comparable in baseline characteristics, with the majority in each group being male (62% of patients receiving the intervention and 68% of those on placebo) and members of each group at similar Child-Pugh stages. The mean age was 59 in the OCR-002 group and 60 in the placebo group.

As for inciting factors, bacterial infection was the most common (found in 29 of the 231 patients in the study), followed by poor compliance (28 patients), dehydration (25 patients), and presence of a transjugular intrahepatic portosystemic shunt (16 patients).

A total of 59 patients in the placebo group completed the 5-day treatment, as did 116 of the treatment group. Reasons for discontinuation included early discharge from the hospital, decision by the investigator, or an adverse event.

The most common adverse events included hypokalemia, pyrexia, urinary tract infection, and anemia. Serious adverse events occurred in 25% of the treatment group and 29% on placebo; mortality rates during the study were 9% in the treatment group and 13% in the placebo group.

Although the primary endpoint of median time to improvement in the intent-to-treat population wasn't statistically significant, the response rate -- defined as time to clinical improvement at 48 hours -- was significantly higher with the study drug than with placebo (P=0.028). In addition, patients on the study drug were discharged from the ICU about 1.5 days earlier, although this finding was not statistically significant.

This work is very important "because for the first time this substance was tested in a very good quality study," said Arnulf Ferlitsch, MD, a hepatologist at the Medical University of Vienna in Austria, who was not involved in the study. "This was always the problem with L-ornithine L-aspartate [a drug with a similar mechanism], that the data are lacking."

Drugs like these are especially needed because hepatic encephalopathy "is a problem which about a third of patients with cirrhosis will have to face, so treating this disease and preventing recurrence is a very important [issue]," Ferlitsch said. "In particular, "it would be a big help for us if we had the substance in oral form for use prophylactically at home by patients."

StephenW

肝性脑病的新型发作快速起作用
研究发现，降低氨水平比标准护理更快

       今天的MedPage新闻编辑Joyce Frieden
    2017年10月22日

    本文是MedPageToday®与Medpage Today之间的合作

动作要点

    请注意，本研究作为摘要发表，并在会议上提出。这些数据和结论应被视为初步的，直到在同行评议期刊上发表。

华盛顿 - 研究人员在这里说，肝病脑病的新治疗工作比通常的护理要快，以减少患者的氨水平。

在基线时诊断为高氨血症的患者中，与安慰剂相比，新型治疗鸟氨酸苯乙酸酯（OCR-002）降低氨水平，导致临床改善更快，改善时间缩短21小时（P = 0.034 ），达拉斯贝勒大学医学中心的Robert Rahimi博士和同事在肝病会议上，美国肝病研究协会年会上发表了海报介绍。

OCR-002“有效地结合氨，这是我们认为是肝性脑病非常重要的治疗机制之一，”负责该试验的Ocera Therapeutics研究合着者兼首席医学官Stanley Bukofzer博士告诉MedPage Today一个采访。 “如果您可以减少这些患者的氨暴露量，您可以挽救病人，让他们了解导致急性加重的所有因素，使他们离开医院，恢复正常的功能。”

他补充说，时间是这种混乱的本质。 “你离开的时间越长[这个问题]，这些患者的风险越高...你想尽可能早地对待病人，[OCR-002]似乎很快就会下降氨。

肝性脑病是肝硬化的严重并发症，每年约有40万例住院病人。总体而言，约15％的经历此事件的患者将会死亡，所以这是一个非常高风险的患者群体。“Bukofzer说。虽然利福昔明通常用于预防，但并不表示住院患者的急性脑病。

研究人员想知道使用新型清除剂机制的OCR-002是否能降低氨水平对这些患者是有帮助的。他们将231例肝硬化患者和2,3或4级肝性脑病急性发作随机分配至OCR-002或安慰剂。由肝衰竭程度确定的药物剂量为10,15或20 g，每天静脉注射5天。

治疗组的基线特征相当，每组中大多数为男性（62％接受干预的患者和68％的安慰剂组），以及每组患儿在类似Child-Pugh阶段。 OCR-002组平均年龄59岁，安慰剂组60例。

对于煽动因素，细菌感染是最常见的（在研究中231例患者中有29例），其次为不良依从（28例），脱水（25例），以及经颈静脉肝内门体分流术（16例） ）。

安慰剂组共有59名患者完成了5天治疗，治疗组116例。停药原因包括早日从医院出院，调查人员作出决定或不良事件。

最常见的不良事件包括低钾血症，发热，尿路感染和贫血。 25％的治疗组发生严重不良事件，安慰剂组为29％研究中死亡率为9％，治疗组为13％，安慰剂组为13％。

虽然意向治疗人群的中位改善时间的主要终点没有统计学意义，但是在48小时内临床改善时间的反应率明显高于安慰剂组P = 0.028）。此外，研究药物的患者在大约1.5天前从ICU出院，尽管这一发现并不具有统计学意义。

这项工作非常重要，因为这种物质首次在非常优质的研究中进行了测试，“奥地利维也纳医科大学肝病专家阿尼尔夫·费利奇（Arnulf Ferlitsch）医生说，他没有参与研究。 “这是L-鸟氨酸L-天冬氨酸（一种具有相似机制的药物）的问题，数据总是缺乏的。”

Ferlitsch说：“肝硬化”是一个大约三分之一的肝硬化患者必须面对的问题，因此治疗这种疾病并防止复发是非常重要的问题。 “特别是，”如果我们口服形式的物质在患者家中预防使用，对我们来说将是一个很大的帮助。“