Background

Faecal microbiota transplantation (FMT) is highly effective for recurrent Clostridioides difficile infection but has inherent risks. Microbial Ecosystem Therapeutic 2 (MET-2) is an oral encapsulated formulation of 40 lyophilised bacterial species initially isolated from stool of a healthy donor, but subsequently manufactured independently of donors, eliminating potential risks introduced by changes in donor health. The aim of this study was to determine MET-2 activity, safety, and tolerability.

Methods

This phase 1, open-label, single-group feasibility study was done in Alberta, Canada. The main inclusion criteria were mild to moderate C difficile infection and at least one episode of C difficile infection recurrence (ie, two episodes of C difficile infection) within 12 months. Initial daily treatment was ten oral capsules for 2 days, then three capsules for 8 days. If C difficile infection recurred, a higher dose was offered: 20 capsules for 2 days, then three capsules for 8 days. Patients were followed for adverse events and C difficile infection recurrence up to day 130. The primary outcome was absence of C difficile infection recurrence (fewer than three unformed bowel movements in 24 h persisting for at least 2 days) at day 40 by intention-to-treat analysis. Secondary outcomes were mortality or hospitalisation due to C difficile infection, infections attributed to treatment, nausea, abdominal pain, vomiting, or diarrhoea during treatment, quality of life (C difficile Health Related Quality of Life Questionnaire) before and after treatment, and engrafted MET-2 bacteria in patient stool. Absence of C difficile infection recurrence at day 130 was an exploratory outcome. This study is registered with ClinicalTrials.gov, NCT02865616

Findings

Between Sept 19, 2018, and Feb 28, 2020, we enrolled 19 adult patients with at least two episodes of mild to moderate C difficile infection (median age 65 years [IQR 56–67]; 12 women [63%], seven men [37%]). Recurrent C difficile infection was absent at day 40 in 15 (79%) of 19 patients after initial treatment, increasing to 18 (95%) 40 days after retreatment. No mortality associated with C difficile infection, infections associated with MET-2 treatment, or other serious adverse events were observed. The most common self-limited, mild to moderate symptoms reported during treatment were diarrhoea in 12 (63%) of 19 patients and abdominal cramps in 12 (63%). After MET-2 treatment, quality of life improved significantly, as did alpha diversity in stool microbial composition (p=1·93×10⁻⁶). MET-2 associated taxa were found in greater abundance in most patients after treatment compared with baseline. 16 (84%) of 19 patients did not have recurrence of C difficile infection by day 130.

Interpretation

MET-2 appears to be safe, efficacious, and well tolerated among patients with recurrent C difficile infection. Results must be validated in controlled studies.

Funding

NuBiyota.

中文翻译：

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微生物生态系统治疗剂（MET-2）对艰难梭状芽胞杆菌反复感染的影响：第1阶段（开放标签，单组试验）

背景

粪便微生物菌群移植（FMT）对于艰难梭状芽胞杆菌反复感染非常有效，但具有固有的风险。微生物生态系统治疗2（MET-2）是40种冻干细菌物种的口服封装制剂，最初从健康供体的粪便中分离出来，但随后独立于供体制造，消除了因供体健康变化而带来的潜在风险。这项研究的目的是确定MET-2活性，安全性和耐受性。

方法

此阶段1，开放标签，单组可行性研究在加拿大艾伯塔省进行。主要纳入标准为轻度至中度艰难梭菌感染，以及在12个月内至少发作一次艰难梭菌感染（即两次艰难梭菌感染）。最初的每日治疗是10粒口服胶囊2天，然后3粒胶囊8天。如果艰难梭菌感染再次发生，则提供更高剂量：20粒胶囊2天，然后3粒胶囊8天。随访患者不良事件和难辨梭状芽胞杆菌感染复发直至第130天。主要结果是不存在难辨梭状芽胞杆菌通过意向性治疗分析，发现感染复发（第24天少于24次少于3次未形成肠蠕动持续至少2天）。次要结果是由于难辨梭状芽胞杆菌感染导致的死亡率或住院，治疗期间的恶心，腹痛，呕吐或腹泻引起的感染，治疗前后的生活质量（艰难梭菌健康相关生活质量问卷）以及移植MET -2患者粪便中有细菌。探索性结局是在第130天没有艰难梭菌感染复发。该研究已在ClinicalTrials.gov注册，NCT02865616

发现

在2018年9月19日至2020年2月28日之间，我们招募了19名成年患者，至少两次发作了轻度至中度C艰难梭菌感染（中位年龄65岁[IQR 56-67]； 12位女性[63％]，七位男性[37％]）。初次治疗后19例患者中有15例（79％）在第40天没有复发性艰难梭菌感染，再治疗40天后增加到18例（95％）。没有与艰难梭菌有关的死亡率观察到感染，与MET-2治疗相关的感染或其他严重不良事件。在治疗期间报告的最常见的自限性轻度至中度症状是腹泻19例中的12例（63％）和腹绞痛12例（63％）。MET-2处理后，生活质量显着提高，粪便微生物组成中的α多样性也显着提高（p = 1·93×10 ^-6）。与基线相比，大多数患者在治疗后发现与MET-2相关的分类单元更为丰富。到第130天时，19例患者中有16例（84％）没有再发生艰难梭菌感染。

解释

MET-2在复发性艰难梭菌感染患者中似乎是安全，有效和耐受的。结果必须在对照研究中得到验证。

资金

NuBiyota。