两项 II 期临床试验的基本原理和研究设计，旨在研究可溶性鸟苷酸环化酶激活剂 BI 685,509 对代偿性肝硬化患者临床显著门静脉高压的影响。
The rationale and study design of two phase II trials examining the effects of BI 685,509, a soluble guanylyl cyclase activator, on clinically significant portal hypertension in patients with compensated cirrhosis.
机构信息
Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria.
出版信息
Trials. 2023 Apr 24;24(1):293. doi: 10.1186/s13063-023-07291-3.
BACKGROUND
Clinically significant portal hypertension (CSPH) drives cirrhosis-related complications (i.e. hepatic decompensation). Impaired nitric oxide (NO) bioavailability promotes sinusoidal vasoconstriction, which is the initial pathomechanism of CSPH development. Activation of soluble guanylyl cyclase (sGC), a key downstream effector of NO, facilitates sinusoidal vasodilation, which in turn may improve CSPH. Two phase II studies are being conducted to assess the efficacy of the NO-independent sGC activator BI 685,509 in patients with CSPH due to various cirrhosis aetiologies.
METHODS
The 1366.0021 trial (NCT05161481) is a randomised, placebo-controlled, exploratory study that will assess BI 685,509 (moderate or high dose) for 24 weeks in patients with CSPH due to alcohol-related liver disease. The 1366.0029 trial (NCT05282121) is a randomised, open-label, parallel-group, exploratory study that will assess BI 685,509 (high dose) alone in patients with hepatitis B or C virus infection or non-alcoholic steatohepatitis (NASH) and in combination with 10 mg empagliflozin in patients with NASH and type 2 diabetes mellitus for 8 weeks. The 1366.0021 trial will enrol 105 patients, and the 1366.0029 trial will enrol 80 patients. In both studies, the primary endpoint is the change from baseline in hepatic venous pressure gradient (HVPG) until the end of treatment (24 or 8 weeks, respectively). Secondary endpoints include the proportion of patients with an HVPG reduction of > 10% from baseline, the development of decompensation events and the change from baseline in HVPG after 8 weeks in the 1366.0021 trial. In addition, the trials will assess changes in liver and spleen stiffness by transient elastography, changes in hepatic and renal function and the tolerability of BI 685,509.
DISCUSSION
These trials will enable the assessment of the short-term (8 weeks) and longer-term (24 weeks) effects and safety of sGC activation by BI 685,509 on CSPH due to various cirrhosis aetiologies. The trials will use central readings of the diagnostic gold standard HVPG for the primary endpoint, as well as changes in established non-invasive biomarkers, such as liver and spleen stiffness. Ultimately, these trials will provide key information for developing future phase III trials.
TRIAL REGISTRATION
1366.0021: EudraCT no. 2021-001,285-38; ClinicalTrials.gov NCT05161481. Registered on 17 December 2021, https://www.
CLINICALTRIALS
gov/ct2/show/NCT05161481 . 1366.0029: EudraCT no. 2021-005,171-40; ClinicalTrials.gov NCT05282121. Registered on 16 March 2022, https://www.
CLINICALTRIALS
gov/ct2/show/NCT05282121 .
背景
临床上显著的门静脉高压症（CSPH）可导致肝硬化相关并发症（即肝功能失代偿）。一氧化氮（NO）生物利用度降低会促进肝窦血管收缩，这是 CSPH 发展的初始病理机制。可溶性鸟苷酸环化酶（sGC）的激活是 NO 的关键下游效应物，可促进肝窦血管舒张，从而可能改善 CSPH。目前正在进行两项 II 期研究，以评估不同病因导致的肝硬化患者中使用非依赖性 sGC 激活剂 BI 685,509 的疗效。
方法
1366.0021 试验（NCT05161481）是一项随机、安慰剂对照、探索性研究，将评估 BI 685,509（中或高剂量）在酒精性肝病导致的 CSPH 患者中使用 24 周。1366.0029 试验（NCT05282121）是一项随机、开放标签、平行组、探索性研究，将评估 BI 685,509（高剂量）单独用于乙型肝炎或丙型肝炎病毒感染或非酒精性脂肪性肝炎（NASH）患者，以及与恩格列净 10mg 联合用于 NASH 和 2 型糖尿病患者 8 周。1366.0021 试验将纳入 105 例患者，1366.0029 试验将纳入 80 例患者。在两项研究中，主要终点均为治疗结束时（分别为 24 或 8 周）肝静脉压力梯度（HVPG）从基线的变化。次要终点包括基线时 HVPG 降低>10%的患者比例、失代偿事件的发生以及 1366.0021 试验中 8 周时 HVPG 从基线的变化。此外，试验还将评估瞬时弹性成像检测的肝、脾硬度变化，肝、肾功能变化以及 BI 685,509 的耐受性。
讨论
这些试验将评估不同病因导致的肝硬化患者中，BI 685,509 短期（8 周）和长期（24 周）作用和安全性。试验将使用 HVPG 的中心读数作为主要终点的诊断金标准，以及肝、脾硬度等既定非侵入性生物标志物的变化。最终，这些试验将为开发未来的 III 期试验提供关键信息。
试验注册
1366.0021：EudraCT 编号 2021-001,285-38；ClinicalTrials.gov NCT05161481。于 2021 年 12 月 17 日注册，https://www.clinicaltrials.gov/ct2/show/NCT05161481。1366.0029：EudraCT 编号 2021-005,171-40；ClinicalTrials.gov NCT05282121。于 2022 年 3 月 16 日注册，https://www.clinicaltrials.gov/ct2/show/NCT05282121。
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