Articles
The effect of a microbial ecosystem therapeutic (MET-2) on recurrent Clostridioides difficile infection: a phase 1, open-label, single-group trial

https://doi.org/10.1016/S2468-1253(21)00007-8Get rights and content

Summary

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.

Introduction

Clostridioides difficile infection is the most common cause of diarrhoea acquired in acute health-care settings. Hospital-acquired C difficile infection increases health-care costs by four times over matched hospitalisation, an added annual cost of US$1 billion in the US and CA$100 million in Canada.1, 2 Within 8 weeks of finishing treatment for C difficile infection, 20–30% of patients will have C difficile infection recurrence with vancomycin or metronidazole. Risk of recurrence increases with each subsequent episode, approaching 60% after a third episode.3, 4, 5, 6 Furthermore, incidence of multiply recurrent C difficile infection is increasing disproportionately to incidence of C difficile infection. Between 2001 and 2012, the incidence of C difficile infection increased by 46%, whereas the incidence of recurrent C difficile infection increased by 189%.7 Although C difficile itself might be suppressed by vancomycin, patients with recurrent C difficile infection continue to experience fatigue, anorexia, weight loss, and reduced quality of life.8 Managing recurrent C difficile infection is a major clinical challenge, because there are few therapeutic options. The result is increased health-care use, costs, and patient suffering.

Research in context

Evidence before this study

We searched MEDLINE for articles published between database inception and Sept 19, 2020, in English with search terms including “Clostridium difficile” or “Clostridiodes difficile”, combined with “fecal microbiota transplant*”, “fecal transplant*”, “microbiome therapeutic*”, “microbial therapeutic*”, “microbiota therapeutic*”, or “microbial ecosystem therapeutic*”. This search yielded 574 results. Randomised controlled trials to date have focused on faecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection. Resolution of recurrent C difficile infection in randomised trials was lower (about 76%) than in open-label studies (about 83%). FMT is not without its clinical challenges, however, because it is undefined, variable, and requires dedicated stool donors with substantial screening of donors for known pathogens. Even with stringent donor selection, when screening and quarantine of donor material between two screening points is correctly done, there is still potential to transmit disease, including antibiotic-resistant organisms and emerging pathogens, such as SARS-CoV-2.

From our literature review, live biotherapeutic products that are under development include stool specimens treated with ethanol (SER-109), microbiota suspension manufactured using standardised processes (RBX2660), and sterile filtrate from donor stool. These products have shown possible effectiveness for recurrent C difficile infection in small phase 1 or 2 trials including 5–40 patients.

Microbial Ecosystem Therapeutic 2 (MET-2) consists of a proprietary consortium of 40 bacterial species derived from the stool of a screened, healthy donor. Strains were highly purified and combined as lyophilised material in capsules for oral delivery. This product does not require further stool donors.

Added value of this study

We assessed the safety, tolerability, and activity of MET-2 in the treatment of recurrent C difficile in a phase 1, single-group trial. This treatment was not associated with any serious adverse events, and 18 (95%) of 19 participants achieved clinical resolution of recurrent C difficile infection. Alpha diversity metrics increased in these patients, and abundances of taxa associated with MET-2 were shown to increase, indicating potential incorporation of MET-2 taxa into patient microbiomes. These findings are similar to those from FMT treatment. This study is also one of the few to assess C difficile ribotypes and toxinotypes throughout its 130-day study period. Patients were infected with a variety of ribotypes and toxinotypes, and ribotype switching occurred in two patients during follow-up. Recurrent C difficile infection resolution was not necessarily associated with clearance of C difficile.

Implications of all the available evidence

There is an unmet need for an effective and safe treatment for recurrent C difficile infection that does not require donor stool, which MET-2 might fulfil. Larger clinical trials are needed to validate these promising results.

Faecal microbiota transplantation (FMT) seems to be the most effective and cost-effective treatment for prevention of recurrent C difficile infection.9, 10 The first randomised trial11 of FMT compared FMT by nasogastric tube with vancomycin and found that a single FMT treatment was 81% efficacious compared with 31% for vancomycin. Further randomised trials showed that FMT is highly efficacious through various delivery routes (colonoscopy 91%,12 enema 85%,13 and oral capsules 96%14) and in various formulations (fresh 100% and frozen-and-thawed 85%).13 Lyophilised FMT capsules have similar efficacy to fresh or frozen FMT (80–90%).15

The short-term safety profile of FMT is favourable, but potential exists for transmission of disease, despite donor screening. In the USA, eight cases of transmission of serious infections through FMT have occurred: two cases of extended spectrum β-lactamase-producing Escherichia coli, two cases of enteropathogenic E coli, and four cases of Shiga toxin-producing E coli. Three patients died in association with these transmissions, prompting warnings from the US Food & Drug Administration (FDA).16, 17, 18, 19, 20 Emergence of novel pathogens (eg, SARS-CoV-2) poses an additional safety hazard, and donor screening protocols must be constantly updated to reflect continually evolving threats. Although these eight cases of transmission could have been prevented with more thorough donor screening, a defined microbiome-derived therapy would mitigate these risks and improve safety.

Petrof and colleagues21 developed a defined microbial consortium (RePOOPulate or Microbial Ecosystem Therapeutic 1 [MET-1]), comprised of 33 bacterial strains derived from stool of a healthy donor. This formulation (100 ml; 3·5 × 109 colony forming units/mL), delivered by colonoscopy, prevented recurrence in two patients with recurrent C difficile infection and demonstrated the feasibility of MET-1 as an alternative to FMT. The latest iteration, MET-2, comprises strains of 40 bacterial species, lyophilised and encapsulated for oral administration. This study was done to determine the safety, activity, and tolerability of MET-2 in recurrent C difficile infection patients.

Section snippets

Study design and participants

In this phase 1, open-label, single-group feasibility study, participants aged 18 years or older with mild to moderate recurrent C difficile infection were recruited at the University of Alberta Hospital (Edmonton, AB, Canada). C difficile infection severity was evaluated clinically in accordance with practice guidelines by the Infectious Diseases Society of America.22 University of Alberta Hospital is a tertiary centre in Alberta providing health care to patients in central and northern

Results

19 patients who met inclusion and exclusion criteria were enrolled (figure 1) between Sept 19, 2018, and Oct 23, 2019, with follow-up to Feb 28, 2020, with 16 (84%) completing the entire study and 17 (90%) completing up to day 40. All 19 patients were included in the analyses. One patient was lost to follow-up after day 40, despite multiple telephone calls to schedule appointments, but this patient had no repeat C difficile testing, prescription for C difficile infection, emergency department

Discussion

In this preliminary study of 19 patients, we showed MET-2 to have activity for treating recurrent C difficile infection in 18 (95%) of 19 of patients, on par with FMT. 15 (79%) of 19 responded after a first treatment, and three (16%) of 19 responded after a second higher-dose treatment course. The one patient who did not respond to two courses of MET-2 opted to withdraw from the study and did not proceed with an offered option of a higher MET-2 dose delivered by colonoscopy. MET-2 is well

Data sharing

Deidentified individual participant data will be made available upon request to the corresponding author with investigator support after approval of a proposal with a signed data access agreement with the University of Alberta.

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