Abstract：
OBJECTIVE: This Phase I study evaluated the safety and early efficacy of an aldosterone synthase inhibitor (BI 690517) in people with diabetes and albuminuric chronic kidney disease.
METHODS: Double-blind, placebo-controlled study (NCT03165240) at 40 sites across Europe. Eligible participants [estimated glomerular filtration rate ≥20 and <75 ml/min/1.73 m2; urine albumin/creatinine ratio (UACR) ≥200 and <3500 mg/g] were randomized 6:1 to receive once-daily oral BI 690517 3, 10 or 40 mg, or eplerenone 25-50 mg, or placebo, for 28 days. The primary endpoint was the proportion of participants with drug-related adverse events (AEs). Secondary endpoints included changes from baseline in the UACR.
RESULTS: Fifty-eight participants were randomized and treated from 27 November 2017 to 16 April 2020 (BI 690517: 3 mg, n = 18; 10 mg, n = 13; 40 mg, n = 14; eplerenone, n = 4; placebo, n = 9) for 28 days. Eight (13.8%) participants experienced drug-related AEs [BI 690517: 3 mg (two of 18); 10 mg (four of 13); 40 mg (two of 14)], most frequently constipation [10 mg (one of 13); 40 mg (one of 14)] and hyperkalaemia [3 mg (one of 18); 10 mg (one of 13)]. Most AEs were mild to moderate; one participant experienced severe hyperkalaemia (serum potassium 6.9 mmol/L; BI 690517 10 mg). UACR responses [≥20% decrease from baseline (first morning void urine) after 28 days] were observed for 80.0% receiving BI 690517 40 mg (eight of 10) versus 37.5% receiving placebo (three of eight). Aldosterone levels were suppressed by BI 690517, but not eplerenone or placebo.
CONCLUSIONS: BI 690517 was generally well tolerated, reduced plasma aldosterone and may decrease albuminuria in participants with diabetes and albuminuric chronic kidney disease.
METHODS: Double-blind, placebo-controlled study (NCT03165240) at 40 sites across Europe. Eligible participants [estimated glomerular filtration rate ≥20 and <75 ml/min/1.73 m2; urine albumin/creatinine ratio (UACR) ≥200 and <3500 mg/g] were randomized 6:1 to receive once-daily oral BI 690517 3, 10 or 40 mg, or eplerenone 25-50 mg, or placebo, for 28 days. The primary endpoint was the proportion of participants with drug-related adverse events (AEs). Secondary endpoints included changes from baseline in the UACR.
RESULTS: Fifty-eight participants were randomized and treated from 27 November 2017 to 16 April 2020 (BI 690517: 3 mg, n = 18; 10 mg, n = 13; 40 mg, n = 14; eplerenone, n = 4; placebo, n = 9) for 28 days. Eight (13.8%) participants experienced drug-related AEs [BI 690517: 3 mg (two of 18); 10 mg (four of 13); 40 mg (two of 14)], most frequently constipation [10 mg (one of 13); 40 mg (one of 14)] and hyperkalaemia [3 mg (one of 18); 10 mg (one of 13)]. Most AEs were mild to moderate; one participant experienced severe hyperkalaemia (serum potassium 6.9 mmol/L; BI 690517 10 mg). UACR responses [≥20% decrease from baseline (first morning void urine) after 28 days] were observed for 80.0% receiving BI 690517 40 mg (eight of 10) versus 37.5% receiving placebo (three of eight). Aldosterone levels were suppressed by BI 690517, but not eplerenone or placebo.
CONCLUSIONS: BI 690517 was generally well tolerated, reduced plasma aldosterone and may decrease albuminuria in participants with diabetes and albuminuric chronic kidney disease.
摘要：
目的：这项I期研究评估了醛固酮合成酶抑制剂（BI690517）在糖尿病和白蛋白尿慢性肾病患者中的安全性和早期疗效。
方法：双盲，在欧洲40个地点进行的安慰剂对照研究（NCT03165240）。符合条件的参与者[估计肾小球滤过率≥20且<75ml/min/1.73m2;尿白蛋白/肌酐比（UACR）≥200且<3500mg/g]随机分为6：1，每天口服一次BI6905173、10或40mg，或者依普利酮25-50毫克,或安慰剂，28天主要终点是药物相关不良事件（AE）的参与者比例。次要终点包括UACR中相对于基线的变化。
结果：从2017年11月27日至2020年4月16日，58名参与者被随机分配并接受治疗（BI690517：3mg，n=18；10毫克，n=13；40毫克，n=14；依普利酮，n=4；安慰剂，n=9)持续28天。八名（13.8％）参与者经历了与药物相关的不良事件[BI690517：3mg（18个中的2个）;10mg（13个中的4个）;40mg（14个中的2个）]，最常见的便秘[10毫克（13之一）;40毫克（14之一）]和高钾血症[3毫克（18之一）;10毫克（13之一）]。大多数不良事件为轻度至中度；一名参与者出现严重的高钾血症（血清钾6.9mmol/L；BI69051710mg）。接受BI69051740mg（10个中的8个）的80.0％与接受安慰剂（8个中的3个）的37.5％的UACR反应[在28天后从基线（第一个早晨的尿液）下降≥20％]。醛固酮水平受BI690517抑制，但依普利酮或安慰剂不抑制。
结论：BI690517总体耐受性良好，在糖尿病和白蛋白尿慢性肾脏疾病参与者中，血浆醛固酮降低，并可能减少白蛋白尿。
方法：双盲，在欧洲40个地点进行的安慰剂对照研究（NCT03165240）。符合条件的参与者[估计肾小球滤过率≥20且<75ml/min/1.73m2;尿白蛋白/肌酐比（UACR）≥200且<3500mg/g]随机分为6：1，每天口服一次BI6905173、10或40mg，或者依普利酮25-50毫克,或安慰剂，28天主要终点是药物相关不良事件（AE）的参与者比例。次要终点包括UACR中相对于基线的变化。
结果：从2017年11月27日至2020年4月16日，58名参与者被随机分配并接受治疗（BI690517：3mg，n=18；10毫克，n=13；40毫克，n=14；依普利酮，n=4；安慰剂，n=9)持续28天。八名（13.8％）参与者经历了与药物相关的不良事件[BI690517：3mg（18个中的2个）;10mg（13个中的4个）;40mg（14个中的2个）]，最常见的便秘[10毫克（13之一）;40毫克（14之一）]和高钾血症[3毫克（18之一）;10毫克（13之一）]。大多数不良事件为轻度至中度；一名参与者出现严重的高钾血症（血清钾6.9mmol/L；BI69051710mg）。接受BI69051740mg（10个中的8个）的80.0％与接受安慰剂（8个中的3个）的37.5％的UACR反应[在28天后从基线（第一个早晨的尿液）下降≥20％]。醛固酮水平受BI690517抑制，但依普利酮或安慰剂不抑制。
结论：BI690517总体耐受性良好，在糖尿病和白蛋白尿慢性肾脏疾病参与者中，血浆醛固酮降低，并可能减少白蛋白尿。
