Safety and efficacy of CRS3123 in adults with a primary episode or first recurrence of Clostridioides difficile infection: a phase 2, randomised, double-blind, multicentre, vancomycin-controlled study

BACKGROUND: CRS3123 is a potent inhibitor of protein synthesis in bacteria that express type 1 methionyl-tRNA ligase, resulting in selective antibacterial activity that holds promise as a novel treatment for Clostridioides difficile infection (CDI). The purpose of this study was to evaluate the safety and efficacy of CRS3123 in adults with a primary episode or first recurrence of CDI. METHODS: This multicentre, randomised, double-blind, vancomycin-controlled, phase 2 study was conducted across 14 enrolling sites in the USA and Canada. Enrolled patients were 18 years or older, with a clinical diagnosis of CDI, including diarrhoea (at least three unformed bowel movements in the 24 h before randomisation) and C difficile toxin A or B, or both, detected in stools. Patients were excluded if they had more than one episode of CDI within the past 3 months or more than two within the past 12 months. Patients were randomly assigned (1:1:1) to receive 10 days of treatment with one of two dose regimens of CRS3123 (200 mg and 400 mg orally twice daily) or oral vancomycin (125 mg orally four times daily). Randomisation used an interactive response technology system and was stratified by history of CDI (first episode vs first recurrence within the past 3-12 months). Masking was maintained by use of matching dummy capsules. Safety was a primary endpoint and was assessed in patients who received at least one dose of study drug. The primary efficacy endpoint was clinical cure (survival and resolution of diarrhoea) at the test-of-cure (TOC) visit (day 12 up to day 15) in the intention-to-treat (ITT) population. The rate of CDI recurrence was a crucial secondary outcome measure assessed at study days 40 and 70 in the microbiological ITT population, which included all patients in the ITT population who tested positively for C difficile toxin at screening or day 1 and who had C difficile isolated in culture. This trial was registered with ClinicalTrials.gov (NCT04781387) and is complete. FINDINGS: Between May 12, 2021, and April 26, 2024, 58 individuals were assessed for eligibility, 43 of whom were recruited and randomly assigned: 14 (33%) to the CRS3123 200 mg group, 15 (35%) to the CRS3123 400 mg group, and 14 (33%) to the vancomycin group. The mean age of patients was 58·4 years (SD 18·0), 33 (77%) patients were female, and ten (23%) patients were male. 31 (72%) patients had a primary episode of CDI and 12 (28%) patients had a first recurrence of CDI. All patients received at least one dose of the assigned drug. Treatment-emergent adverse events (TEAEs) were mild to moderate in severity and similar across treatment groups. TEAEs considered possibly related to study drug (all grade 1 or 2) were reported in one patient in the CRS3123 200 mg group (dry mouth, asthenia and gastro-oesophageal reflux disease, nausea, vomiting, increased alanine aminotransferase, and increased aspartate aminotransferase), three patients in the CRS3123 400 mg group (one with increases in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase; one with malaise, nausea, and feeling abnormal; and one with headache); and in no patients in the vancomycin group. The only serious adverse event reported, pneumonia, was in the vancomycin group and was considered unrelated to the study drug. 13 (93%) of 14 patients in the CRS3123 200 mg group, all 15 (100%) patients in the CRS3123 400 mg group, and 13 (93%) of 14 patients in the vancomycin group had clinical cure at the TOC visit. No patient had clinical failure at the TOC visit; two patients (one each in the CRS3123 200 mg and vancomycin groups) had indeterminate responses due to missing data. Recurrence through day 40 occurred in one (7%) of 14 patients in the CRS3123 400 mg group, none of the 13 patients in the CRS3123 200 mg group, and three (23%) of 13 patients in the vancomycin group, and there was an additional recurrence on day 70 in the CRS3123 400 mg group. INTERPRETATION: Both doses of CRS3123 were deemed safe and well tolerated and showed efficacy similar to vancomycin at the TOC visit, with lower rates of recurrence. Together, these data support further development of CRS3123. FUNDING: US National Institute of Allergy and Infectious Diseases at the National Institutes of Health, Department of Health and Human Services.