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An oral, investigational live biotherapeutic product containing eight strains of commensal Clostridia prevented recurrent Clostridioides difficile infections in a randomized, double-blind phase II trial.

In the 79-participant study, recurrences at 8 weeks using a combined laboratory and clinical definition were detected in 13.8% of those who received high-dose VE303, as compared with 45.5% of those assigned to placebo (P=0.006), reported Jeffrey Silber, MD, of Vedanta Biosciences in Cambridge, Massachusetts, and colleagues.

The recurrence rate in a low-dose VE303 arm of the study (37%) was not significantly better than placebo (P=0.30), according to the findings in , which were also presented at the in Copenhagen, Denmark.

"In the high-dose VE303 group, all CDI [C. difficile infection] recurrences through week 8 occurred by day 11, likely due to subsequent colonization of VE303 strains and VE303-induced restoration of the gut microbiota community," wrote Silber and co-authors. "Most participants experienced sustained cure through week 24, suggesting that VE303 has a durable effect."

VE303 strains colonized rapidly during the 14-day dosing period, the researchers said, and "participants with high VE303 colonization had a lower probability of CDI recurrence than those with low colonization, suggesting a positive exposure-response relationship."

Derived from healthy human stool samples, Silber's group explained that "VE303 is a defined bacterial consortium composed of eight well-characterized, nonpathogenic, nontoxigenic, commensal strains of Clostridia" -- five strains from cluster XIVa, two from cluster IV, and one from cluster XVII.

They said the low recurrence rate with high-dose VE303 as well as the absolute risk reduction of 30.5% versus placebo compare favorably to other microbiota products tested in trials, including the first-ever product approved by the FDA last December for preventing recurrent C. difficile infections.

The current from Silber and colleagues was conducted from February 2019 to September 2021 in Canada and the U.S., randomly assigning 29 adult patients with C. difficile infections to high-dose VE303 (8 × 10⁹ colony-forming units [CFUs]), 27 to low-dose VE303 (1.6 × 10⁹ CFUs), and 22 to placebo, all delivered orally once-daily for 14 days.

Criteria for enrollment included patients having had one or more laboratory-confirmed C. difficile infections within the last 6 months, or those deemed to be at high risk for recurrence -- age 75 or older; or age 65 to under 75 but with creatinine clearance below 60 mL/min/1.73 m², proton pump inhibitor use, and history of a C. difficile infection more than 6 months ago.

Participants had a median age of 63.5 years, 70.5% were women, and the vast majority were white (96.2%).

Most (72%) were treated with vancomycin during their qualifying C. difficile infection episode, and 21% received fidaxomicin, mirroring current practice, according to Silber and colleagues.

The primary 8-week efficacy analysis for recurrence included three definitions, with each involving diarrhea consistent with a C. difficile infection plus:

• A toxin-positive stool sample
• A toxin-positive stool sample or positive polymerase chain reaction (PCR) test result
• A toxin-positive stool sample or PCR test result plus participants treated with an antibiotic for a C. difficile infection but who did not have a confirmatory laboratory test

Under the first definition (toxin-positive stool sample), recurrence rates were 13.8% with high-dose VE303 and 22.7% with placebo, a non-significant difference. Under the second definition (toxin-positive stool sample or positive PCR), these rates were 13.8% and 36.4%, respectively, representing a significant absolute adjusted risk reduction of 21.1% (95% CI 3-42).

The third definition, which uses a combined laboratory and clinical approach, represents "a pragmatic approach used clinically" and endorsed by guidelines, the researchers said, though they acknowledged this could be seen as a limitation, as two recurrences were diagnosed without a positive laboratory test.

Secondary endpoints included recurrences out to week 24 as well as stool microbiome endpoints (VE303 strain colonization, fecal microbiome diversity). In follow-up through week 24, there were two more recurrences, one in each of the VE303 groups.

Treatment-emergent adverse events (AEs) were reported in 53.3% of the high-dose VE303 group, 29.6% of the low-dose group, and 31.8% of the placebo group, with the majority of VE303 events being gastrointestinal and mild in intensity.

Approximately 10% of patients in the VE303 groups reported a severe or serious treatment-emergent AE. Four patients in the high-dose group discontinued due to an AE, as well as two in the low-dose group and one in the placebo group.

Other limitations cited by the authors included issues surrounding testing accuracy, enrollment problems due to the pandemic, and the "availability of open-label fecal microbial transplant in many areas." Noting the predominantly white patient population as well, Silber's group said an adequately sized and powered phase III trial is being planned "with an emphasis on enrolling a more diverse study population."

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