Abstract

Background

Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs.

Methods

In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed.

Results

89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity.

Conclusions

Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial.

Clinical Trials Registration

NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.

中文翻译：

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SER-109，一种在研微生物组药物，可减少艰难梭菌感染后的复发：从 2 期试验中吸取的经验教训

 抽象的

 背景

复发性艰难梭菌感染 (rCDI) 与微生物多样性和微生物衍生的次级胆汁酸的丧失有关，后者会抑制艰难梭菌的发芽和生长。 SER-109 是一种来自供体的纯化孢子的研究性微生物组药物，在一项针对患有多种 rCDI 的受试者的剂量范围 (P) 1 期研究中，它减少了复发。

 方法

在一项 P2 双盲试验中，对标准护理抗生素临床缓解的受试者按年龄（< 或≥65 岁）进行分层，并按 2:1 随机分配至单剂量 SER-109 或安慰剂。受试者在研究开始时通过 PCR 或毒素检测进行诊断。对安全性、第 8 周艰难梭菌阳性腹泻、SER-109 植入和胆汁酸变化进行了评估。

 结果

89 名受试者入组（67% 为女性；80.9% 通过 PCR 诊断）。 SER-109 组的 rCDI 率低于安慰剂组（44.1% vs 53.3%），但未达到统计学显着性。在一项预先计划的分析中，≥65 岁受试者的发生率有所降低（分别为 45.2% vs 80%；RR，1.77；95% CI，1.11–2.81），而 <65 组则没有显示出任何获益。 SER-109 的早期植入与不复发 (P < .05) 和次级胆汁酸浓度增加 (P < .0001) 相关。这项研究和 P1 研究的全宏基因组测序揭示了以前未被认识到的剂量依赖性植入动力学，并证实了早期植入和不复发之间的关联。植入动力学表明 P2 剂量不是最理想的。不良事件的严重程度一般为轻度至中度。

 结论

早期 SER-109 植入与 CDI 复发率降低相关，并且观察到良好的安全性。当前的 P3 试验中实施了更高剂量的 SER-109 和毒素检测要求。

临床试验注册

NCT02437487，https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw=2&rank=4。