A double-blind, randomized, placebo-controlled, phase 2 trial examined the efficacy and safety of monlunabant in adults with diabetic kidney disease.

Here, we investigated the efficacy and safety of monlunabant, a second-generation cannabinoid receptor 1 inverse agonist, in individuals with DKD.

在这里，我们研究了第二代大麻素受体1拮抗剂monlunabant在糖尿病肾病患者中的疗效和安全性。

Methods

This phase 2, randomized, double-blind, placebo-controlled, multicenter study, enrolled adults with DKD.

这项第二阶段、随机、双盲、安慰剂对照的多中心研究，招募了患有糖尿病肾病（DKD）的成年人。

Participants were randomized (1:1:1) to receive oral tablets of monlunabant 10 mg or 25 mg, or placebo once daily for 16 weeks.

参与者被随机分为三组（1:1:1），分别接受每日一次口服10毫克或25毫克的monlunabant片剂，或安慰剂，持续16周。

The primary endpoint was the change in urine albumin-to-creatinine ratio (UACR) from baseline to week 16.

主要终点是基线至第16周尿白蛋白与肌酐比值（UACR）的变化。

Secondary endpoints included changes in urine protein-to-creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR).

次要终点包括尿蛋白与肌酐比值（UPCR）和估算的肾小球滤过率（eGFR）的变化。

Results

In total, 254 participants formed the full analysis set (85, 86, and 83 in the 10 mg, 25 mg, and placebo groups, respectively).

共有254名参与者构成了完整分析集（分别有85名、86名和83名在10毫克、25毫克和安慰剂组）。

At week 16, the estimated geometric least squares mean ratios to baseline for UACR were 0.58, 0.51, and 0.71 in the 10 mg, 25 mg, and placebo groups, respectively.

在第16周，尿白蛋白/肌酐比值（UACR）相对于基线的估计几何最小二乘均值比分别为10毫克组0.58、25毫克组0.51和安慰剂组0.71。

Monlunabant 25 mg did not show statistically significant differences compared to placebo (estimated treatment ratio [ETR] 0.72, 95% confidence interval(0.46 to 1.14)).

Monlunabant 25 mg 与安慰剂相比未显示出统计学上的显著差异（估计治疗比[ETR] 0.72, 95% 置信区间 (0.46 到 1.14)）。

Therefore, formal testing was not performed for 10 mg compared to placebo (ETR 0.82 (0.53 to 1.27)).

因此，与安慰剂相比，10 mg 的正式测试未被执行（ETR 0.82 (0.53 到 1.27)）。

Secondary endpoints showed similar trends, with no differences in UPCR or eGFR, when compared to placebo.

次要终点显示了类似的趋势，与安慰剂相比，尿蛋白肌酐比（UPCR）或估算肾小球滤过率（eGFR）没有差异。

The most frequently reported adverse events were mild to moderate gastrointestinal disorders, driven by nausea, vomiting, and diarrhea.

最常报告的不良事件是轻度至中度的胃肠道疾病，主要由恶心、呕吐和腹泻引起。

Participant withdrawals increased with monlunabant dose.

随着monlunabant剂量的增加，参与者的退出人数也随之增加。

Conclusions

Our study failed to establish proof of concept of monlunabant in DKD, as the effect on UACR at week 16 was not significantly different from placebo.

我们的研究未能证明monlunabant在糖尿病肾病（DKD）中的概念验证，因为在第16周时，其对尿白蛋白/肌酐比值（UACR）的影响与安慰剂相比没有显著差异。

However, greater than anticipated variability and a large placebo response affect interpretation.

然而，超出预期的变异性以及较大的安慰剂反应影响了解释。

trial_registration

Registered at ClinicalTrials.gov with study number NCT05514548.

已在ClinicalTrials.gov注册，研究编号为NCT05514548。