Purpose

Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin.

Methods

Phase-2a, double-blind, randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality.

Results

301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI −1.93–0.49, p = 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo [difference at 0.76 (95% CI 0.18–1.35); p = 0.007]. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53–1.31, log-rank p = 0.44).

Conclusions

Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.

中文翻译：

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非中和性肾上腺髓质素抗体 adrecizumab (HAM8101) 在感染性休克患者中的安全性和耐受性：AdrenOSS-2 2a 期生物标志物指导试验

目的

在高肾上腺髓质素的感染性休克患者中研究人源化单克隆肾上腺髓质素抗体 adrecizumab 的安全性和耐受性。

方法

与安慰剂相比，单次输注阿德瑞珠单抗（2 或 4 毫克/千克体重）的 2a 期、双盲、随机、安慰剂对照生物标志物指导试验。肾上腺髓质素高于 70 pg/mL 且因感染性休克而开始使用血管加压药 < 12 小时的患者符合条件。随机化为 1:1:2。记录主要安全性（90 天死亡率、治疗紧急不良事件 (TEAE)）和耐受性（药物中断、血流动力学）终点。疗效终点包括脓毒症支持指数（SSI，反映无呼吸机和无休克的存活天数）、顺序相关器官衰竭评估（SOFA）的变化和 28 天死亡率。

结果

招募了 301 名患者（血管加压药开始后的中位时间为 8.5 小时）。Adrecizumab 耐受性良好（一次中断，无血流动力学改变），治疗组之间 TEAE 的频率和严重程度没有差异（3 级或更高级别的 TEAE：adrecizumab 组为 70.5%，安慰剂组为 71.1%）和 90-日死亡率。adrecizumab 和安慰剂之间 SSI 变化的差异为 0.72（CI -1.93–0.49，p  = 0.24）。在各种次要终点中，与安慰剂相比，adrecizumab 联合组的 delta SOFA 评分（定义为最大与最小 SOFA）更明显[差异为 0.76（95% CI 0.18-1.35）；p = 0.007]。阿德瑞珠单抗组的 28 天死亡率为 23.9%，安慰剂组为 27.7%，风险比为 0.84（95% 置信区间 0.53-1.31，对数秩p  = 0.44）。

结论

总体而言，我们成功完成了一项随机试验，评估选择具有疾病相关生物标志物的患者进行登记。使用两剂肾上腺髓质素抗体 adrecizumab 没有明显的危害信号；然而，需要进一步的随机对照试验来证实这种药物在感染性休克患者中的有效性和安全性。