VE303, a Defined Bacterial Consortium, for Prevention of Recurrent Clostridioides difficile Infection

Abstract

ImportanceThe effect of rationally defined nonpathogenic, nontoxigenic, commensal strains of Clostridia on prevention of Clostridioides difficile infection (CDI) is unknown.ObjectiveTo determine the efficacy of VE303, a defined bacterial consortium of 8 strains of commensal Clostridia, in adults at high risk for CDI recurrence. The primary objective was to determine the recommended VE303 dosing for a phase 3 trial.Design, Setting, and ParticipantsPhase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from February 2019 to September 2021 at 27 sites in the US and Canada. The study included 79 participants aged 18 years or older who were diagnosed with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence (defined as aged ≥75 years or ≥65 years with ≥1 risk factors: creatinine clearance <60 mL/min/1.73 m2, proton pump inhibitor use, remote [>6 months earlier] CDI history).InterventionsParticipants were randomly assigned to high-dose VE303 (8.0 × 109 colony-forming units [CFUs]) (n = 30), low-dose VE303 (1.6 × 109 CFUs) (n = 27), or placebo capsules (n = 22) orally once daily for 14 days.Main Outcomes and MeasuresThe primary efficacy end point was the proportion of participants with CDI recurrence at 8 weeks using a combined clinical and laboratory definition. The primary efficacy end point was analyzed in 3 prespecified analyses, using successively broader definitions for an on-study CDI recurrence: (1) diarrhea consistent with CDI plus a toxin-positive stool sample; (2) diarrhea consistent with CDI plus a toxin-positive, polymerase chain reaction–positive, or toxigenic culture–positive stool sample; and (3) diarrhea consistent with CDI plus laboratory confirmation or (in the absence of a stool sample) treatment with a CDI-targeted antibiotic.ResultsBaseline characteristics were similar across the high-dose VE303 (n = 29; 1 additional participant excluded from efficacy analysis), low-dose VE303 (n = 27), and placebo (n = 22) groups. The participants’ median age was 63.5 years (range, 24-96); 70.5% were female; and 1.3% were Asian, 1.3% Black, 2.6% Hispanic, and 96.2% White. CDI recurrence rates through week 8 (using the efficacy analysis 3 definition) were 13.8% (4/29) for high-dose VE303, 37.0% (10/27) for low-dose VE303, and 45.5% (10/22) for placebo (P = .006, high-dose VE303 vs placebo).Conclusions and RelevanceAmong adults with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence, high-dose VE303 prevented recurrent CDI compared with placebo. A larger, phase 3 study is needed to confirm these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT03788434

PersonalizedClostridioides difficileengraftment risk prediction and probiotic therapy assessment in the human gut

“…The probiotic, referred to as VE303, was composed of 8 commensal Clostridia strains and shown to be effective at treating CDI in mice 9 . This probiotic was also shown to be safe and well-tolerated and effective in reducing rCDI incidence in humans 10 .…”

Future Microbiome Therapeutics for Clostridioides difficile Infection

“…VE303, developed by Vedanta Biosciences, is a rationally selected bacterial consortium composed of 8 well-characterized, nonpathogenic, nontoxigenic, commensal Clostridia strains in an encapsulated oral formulation (5). A multicenter phase 2 clinical trial evaluated the efficacy of VE303 in preventing recurrence in adults with recurrent CDI or with primary CDI at high risk of recurrence (defined as aged 75 years or older or 65 years or older with $1 risk factors: creatinine clearance ,60 mL/min/1.73 m 2 , proton pump inhibitor use, or remote [.6 months earlier]) CDI (6). Seventy-nine participants with laboratory-confirmed CDI and an adequate response to standard-of-care antibiotic therapy were randomized to receive either a high-dose VE303 (8.0 3 109 colony-forming units [CFU], 10 capsules), low-dose VE303 (1.6 3 109 CFU, 2 capsules), or placebo orally once daily for 14 days.…”

Microbiota-Based Therapeutics as New Standard-of-Care Treatment for Recurrent <i>Clostridioides difficile</i> Infection

“…Ongoing clinical trials are investigating additional candidates for microbiotabased therapies. These explore innovative approaches, such as bacteria cultured in vitro (NTCD-M3) or a defined combination of 8 bacterial strains (VE303), all tailored for oral administration [50,51].…”