背景:过量醛固酮加速慢性肾脏病进展。这项2期临床试验评估了醛固酮合酶抑制剂BI690517,对于功效,安全,和剂量选择。
方法:这是一家跨国公司,随机化,控制,第二阶段试验。年龄在18岁或以上的人,估计肾小球滤过率(eGFR)为30至90mL/min/1·73m2,尿白蛋白与肌酐之比(UACR)为200至5000mg/g,和4·8mmol/L或更低的血清钾,服用血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂,已注册。参与者被随机分配(1:1)到8周的empagliflozin或安慰剂磨合,随后进行第二次随机分组(1:1:1:1)至14周,每天一次,剂量为3mg的BI690517,10毫克,或20毫克,或安慰剂。研究参与者,研究协调员,调查员,数据协调中心被掩盖在治疗分配中。主要终点是从基线(第二次随机分组)到治疗结束的第一天早晨尿液中测量的UACR的变化。本研究已在ClinicalTrials.gov(NCT05182840)注册并完成。
结果:在2022年2月18日至12月30日之间,714名跑步参与者,586人被随机分配接受BI690517或安慰剂。在基线,33%(n=196)是女性,67%(n=390)是男性,42%(n=244)有白人以外的种族身份,参与者平均年龄为63·8岁(SD11·3)。平均基线eGFR为51·9mL/min/1·73m2(17·7),中位UACR为426mg/g(IQR205至889)。安慰剂治疗从基线到第14周治疗结束的第一天早晨无效UACR的百分比变化为-3%(95%CI-19至17),-22%(-36至-7),BI6905173毫克,-39%(-50至-26),BI69051710毫克,-37%(-49至-22)使用BI69051720mg单药治疗。当添加到empagliflozin时,BI690517产生类似的UACR降低。研究者报告的高钾血症发生在10%(14/146)的那些在BI6905173mg组,BI69051710mg组中15%(22/144),在BI69051720mg组中占18%(26/146),在接受安慰剂的人中,有6%(147人中有9人),有或没有empagliflozin。大多数高钾血症患者不需要干预(86%[72/84])。在436名接受BI690517的研究参与者中,有7名(2%)和147名接受匹配安慰剂的参与者中的1名(1%),肾上腺功能不全是一个特别关注的不良事件。在研究期间没有发生与治疗相关的死亡。
结论:BI690517剂量依赖性地减少蛋白尿,同时抑制肾素-血管紧张素系统和依帕列净,提示慢性肾脏病治疗的附加疗效没有意外的安全信号。
背景:勃林格红.
BACKGROUND: Excess aldosterone accelerates chronic kidney disease progression. This phase 2 clinical
trial assessed BI 690517, an aldosterone synthase inhibitor, for efficacy, safety, and dose selection.
METHODS: This was a multinational, randomised, controlled, phase 2
trial. People aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 30 to less than 90 mL/min/1·73 m2, a urine albumin to creatinine ratio (UACR) of 200 to less than 5000 mg/g, and serum potassium of 4·8 mmol/L or less, taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, were enrolled. Participants were randomly assigned (1:1) to 8 weeks of empagliflozin or placebo run-in, followed by a second randomisation (1:1:1:1) to 14 weeks of treatment with once per day BI 690517 at doses of 3 mg, 10 mg, or 20 mg, or placebo.
Study participants, research coordinators, investigators, and the data coordinating centre were masked to treatment assignment. The primary endpoint was the change in UACR measured in first morning void urine from baseline (second randomisation) to the end of treatment. This
study is registered with ClinicalTrials.gov (NCT05182840) and is completed.
RESULTS: Between Feb 18 and Dec 30, 2022, of the 714 run-in participants, 586 were randomly assigned to receive BI 690517 or placebo. At baseline, 33% (n=196) were women, 67% (n=390) were men, 42% (n=244) had a racial identity other than White, and mean participant age was 63·8 years (SD 11·3). Mean baseline eGFR was 51·9 mL/min/1·73 m2 (17·7) and median UACR was 426 mg/g (IQR 205 to 889). Percentage change in first morning void UACR from baseline to the end of treatment at week 14 was -3% (95% CI -19 to 17) with placebo, -22% (-36 to -7) with BI 690517 3 mg, -39% (-50 to -26) with BI 690517 10 mg, and -37% (-49 to -22) with BI 690517 20 mg monotherapy. BI 690517 produced similar UACR reductions when added to empagliflozin. Investigator-reported hyperkalaemia occurred in 10% (14/146) of those in the BI 690517 3 mg group, 15% (22/144) in the BI 690517 10 mg group, and 18% (26/146) in the BI 690517 20 mg group, and in 6% (nine of 147) of those receiving placebo, with or without empagliflozin. Most participants with hyperkalaemia did not require intervention (86% [72/84]). Adrenal insufficiency was an adverse event of special interest reported in seven of 436 study participants (2%) receiving BI 690517 and one of 147 participants (1%) receiving matched placebo. No treatment-related deaths occurred during the
study.
CONCLUSIONS: BI 690517 dose-dependently reduced albuminuria with concurrent renin-angiotensin system inhibition and empagliflozin, suggesting an additive efficacy for chronic kidney disease treatment without unexpected safety signals.
BACKGROUND: Boehringer Ingelheim.