ticipants with prespecified reductions in eGFR at weeks 24 and 48 were not significantly different for lademirsen versus placebo. Background Preclinical models of disease have suggested that targeting microRNA-21 (miRNA-21) may slow the decline in kidney function in individuals with Alport syndrome (AS). The objective of this study was to investigate the effects of the anti–miRNA-21 oligonucleotide, lademirsen, on rate of eGFR decline in adults with AS at risk of rapid disease progression. Methods This study was a phase 2 trial of lademirsen, with a randomized, double-blind, placebo-controlled period followed by an open-label period. Adults with AS, eGFR >35 to <90 ml/min per 1.73 m2, and evidence of rapidly progressive kidney dysfunction were randomized 2:1 to lademirsen 110 mg subcutaneously once weekly or placebo for 48 weeks. After a planned interim analysis (after 24 of 43 randomized participants completed the week 48 study visit or discontinued before week 48), the trial was terminated for futility. Results Forty-three adults with AS (26 men, 17 women) participated (mean age 34 years), and 28 (lademirsen: n=19; placebo: n=9) completed 48 weeks of double-blind treatment. All participants in both groups developed treatment-emergent adverse events, mainly respiratory tract infections, headache, dizziness, metabolic/electrolyte disturbances, and anemia. Treatment was discontinued in three lademirsen-treated participants in the double-blind period and one participant in the open-label period, owing to treatment-emergent adverse events. The least squares mean eGFR slope (95% confidence interval) over 48 weeks in the lademirsen and placebo groups was −5 (−8.7 to −1.1) and −5 (−10.2 to 0.8) ml/min per 1.73 m2 per year, respectively. No significant differences between groups were identified in eGFR at any timepoint or in proportion of participants with prespecified reductions in eGFR at week 24 or 48. Conclusions While anti–miRNA-21 therapy with lademirsen was generally well-tolerated with an acceptable safety profile, no meaningful improvement in rate of kidney function decline in adults with AS at risk of rapidly progressive disease was observed. Clinical Trial registration number: NCT02855268....

中文翻译：

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随机对照临床试验检测拉德米尔森对阿尔波特综合征成人肾功能下降的影响


与安慰剂相比，在第 24 周和第 48 周时 eGFR 预先设定降低的参与者并没有显着差异。背景疾病的临床前模型表明，针对 microRNA-21 (miRNA-21) 可能会减缓 Alport 综合征 (AS) 患者肾功能的下降。本研究的目的是调查抗 miRNA-21 寡核苷酸 Lademirsen 对患有疾病快速进展风险的成人 AS 的 eGFR 下降率的影响。方法 本研究是 lademirsen 的一项 2 期试验，具有随机、双盲、安慰剂对照期，随后是开放标签期。患有 AS、eGFR >35 至 <90 ml/min/1.73 m2 且有快速进展性肾功能不全证据的成人按 2:1 比例随机分配至 lademirsen 110 mg 皮下注射组，每周一次，或安慰剂组，持续 48 周。在计划的中期分析后（43 名随机参与者中的 24 名完成第 48 周的研究访视或在第 48 周之前终止），试验因无效而终止。结果 43 名 AS 成人（26 名男性，17 名女性）参与（平均年龄 34 岁），其中 28 名（拉德米尔森：n=19；安慰剂：n=9）完成了 48 周的双盲治疗。两组的所有参与者都出现了治疗引起的不良事件，主要是呼吸道感染、头痛、头晕、代谢/电解质紊乱和贫血。由于治疗中出现的不良事件，三名接受拉德米尔森治疗的受试者在双盲期和一名受试者在开放标签期停止治疗。拉德米尔森组和安慰剂组 48 周内的最小二乘平均 eGFR 斜率（95% 置信区间）分别为每年每 1.73 平方米 -5（-8.7 至 -1.1）和 -5（-10.2 至 0.8）ml/min 。 在任何时间点的 eGFR 或在第 24 周或第 48 周时预先指定 eGFR 降低的参与者比例方面，各组之间均未发现显着差异。结论 虽然使用 lademirsen 进行抗 miRNA-21 治疗通常耐受性良好且安全性可接受，但没有发现观察到患有疾病快速进展风险的成人 AS 的肾功能下降率显着改善。临床试验注册号：NCT02855268....