Analysis of C. difficile infection-related outcomes in European participants in the bezlotoxumab MODIFY I and II trials

Abstract

The MODIFY I/II trials demonstrated that bezlotoxumab, a human monoclonal antibody against Clostridioides difficile toxin B, given during antibiotic treatment for Clostridioides difficile infection (CDI) significantly reduced C. difficile recurrence (rCDI) in adults at high risk for rCDI. Efficacy of CDI-directed intervention may depend on ribotype regional epidemiology, and patient characteristics. This post hoc analysis assessed the efficacy of bezlotoxumab in the subgroup of MODIFY I/II trial participants enrolled in Europe. Data from the bezlotoxumab (10 mg/kg single intravenous infusion) and placebo (0.9% saline) groups from MODIFY I/II were compared to assess initial clinical cure (ICC), rCDI, all-cause, and CDI-associated rehospitalizations within 30 days of discharge, and mortality through 12 weeks post-infusion. Of 1554 worldwide participants, 606 were from Europe (bezlotoxumab n = 313, 51%; placebo n = 292; 48%). Baseline characteristics were generally similar across groups, although there were more immunocompromised participants in the bezlotoxumab group (27.2%) compared with placebo (20.1%). Fifty-five percent of participants were female, and 86% were hospitalized at randomization. The rate of ICC was similar between treatment groups. The rate of rCDI in the bezlotoxumab group was lower compared with placebo among European participants overall, and among those with ≥ 1 risk factor for rCDI. Bezlotoxumab reduced 30-day CDI-associated rehospitalizations compared with placebo. These results are consistent with overall results from the MODIFY trials and demonstrate that bezlotoxumab reduces rCDI and CDI-associated rehospitalizations in European patients with CDI. MODIFY I/II (NCT01241552 and NCT01513239).

Keywords: Bezlotoxumab; CDI recurrence; Clostridioides difficile infection; Rehospitalization.

Conflict of interest statement

EB has participated in clinical trials and advisory boards sponsored by MSD, Pfizer, and Astellas. ARM has participated in clinical trials sponsored by MSD. RP has participated in clinical trials sponsored by MSD. OAC has received research grants from, is an advisor to, or received lecture honoraria from Actelion, Allecra Therapeutics, Amplyx, Arsanis, Astellas, AstraZeneca, Basilea, Bayer, Cidara, Da Volterra, F2G, Gilead, GSK, IQVIA, Janssen, Leeds University, Matinas, The Medicines Company, Medpace, Melinta, Menarini, MSD, Miltenyi, Paratek, Pfizer, PSI, Rempex, Roche, Sanofi Pasteur, Scynexis, Seres, Summit, Tetraphase, and Vical. MCE, MEH, and MBD are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or restricted stock units in Merck & Co., Inc., Kenilworth, NJ, USA.

Figures

Fig. 1

Number and proportion of participants enrolled in the European region shown by country in MODIFY I and MODIFY II (mITT population; numbers represent n’s)

Fig. 2

Proportion of participants with ICC and SCC (mITT population) and rCDI (clinical cure population). Numbers above bars indicate difference and 95% confidence interval. All, all European participants; ≥ 1 risk factor, European participants with at least 1 risk factor for CDI recurrence (≥ 65 years of age, ≥ 1 CDI episodes in past 6 months, severe CDI (Zar score ≥ 2), immunocompromised, ribotypes 027, 078, or 244 strain; BEZ, bezlotoxumab; CI, confidence interval; ICC, initial clinical cure; mITT, modified intent-to-treat; PBO, placebo; rCDI, recurrent Clostridium difficile infection; SCC, sustained clinical cure

Fig. 3

C. difficile infection recurrence rates by risk factor subgroup in European participants (clinical cure population). Unless otherwise specified, each subgroup includes all patients with the risk factor(s) (i.e., those with only the specified risk factor[s] and those with the specified risk factor[s] and ≥ 1 additional risk factor). CDI Hx, Clostridium difficile infection history in the previous 6 months; CI, confidence interval. aBased on Miettinen and Nurminen method without stratification. bZar score ≥ 2 based on the following: (1) age > 60 years (1 point); (2) body temperature > 38.3 °C (> 100 °F) (1 point); (3) albumin level ˂ 2.5 mg/dL (1 point); (4) peripheral WBC count > 15,000 cells/mm3 within 48 h (1 point); (5) endoscopic evidence of pseudomembranous colitis (2 points); and (6) treatment in an intensive care unit (2 points). cDefined on the basis of a subject’s medical history or use of immunosuppressive therapy. dDenominator is subjects in the mITT population with a positive culture

Fig. 4

Kaplan-Meier plot of time to CDI recurrence