Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence

Abstract

Background: Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B indicated to prevent C. difficile infection (CDI) recurrence (rCDI) in adults at high risk for rCDI. This post hoc analysis of pooled monocolonal antibodies for C.difficile therapy (MODIFY) I/II data assessed bezlotoxumab efficacy in participants with characteristics associated with increased risk for rCDI.

Methods: The analysis population was the modified intent-to-treat population who received bezlotoxumab or placebo (n = 1554) by risk factors for rCDI that were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of participants with rCDI in 12 weeks, fecal microbiota transplant procedures, 30-day all cause and CDI-associated hospital readmissions, and mortality at 30 and 90 days after randomization were presented.

Results: The majority of enrolled participants (75.6%) had ≥1 risk factor; these participants were older and a higher proportion had comorbidities compared with participants with no risk factors. The proportion of placebo participants who experienced rCDI exceeded 30% for each risk factor compared with 20.9% among those without a risk factor, and the rCDI rate increased with the number of risk factors (1 risk factor: 31.3%; ≥3 risk factors: 46.1%). Bezlotoxumab reduced rCDI, fecal microbiota transplants, and CDI-associated 30-day readmissions in participants with risk factors for rCDI.

Conclusions: The risk factors prespecified in the MODIFY statistical analysis plan are appropriate to identify patients at high risk for rCDI. While participants with ≥3 risk factors had the greatest reduction of rCDI with bezlotoxumab, those with 1 or 2 risk factors may also benefit.

Clinical trials registration: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).

Figures

Figure 1.

A, Proportion of participants with Clostridium difficile infection (CDI) recurrence, by prespecified risk factor. Each subgroup includes all participants with the risk factor (ie, those with only 1 risk factor and those with the specified risk factor and ≥1 additional risk factor). B, Proportion of participants with CDI recurrence, by number of prespecified risk factors (clinical cure population). Difference and 95% confidence intervals, shown above bars, were based on the Miettinen and Nurminen method. Prespecified risk factors include age ≥65 years, history of CDI in the previous 6 months, immunocompromised, severe CDI, and having a strain associated with poor outcomes of CDI (ribotype 027, 078, or 244). †CDI history in the previous 6 months. ‡Defined on the basis of a subject’s medical history or use of immunosuppressive therapy. §Based on the Zar score, scored as (1) age >60 years (1 point); (2) body temperature >38.3°C (>101°F) (1 point); (3) albumin level <2.5 g/dL (1 point); (4) peripheral white blood cell count >15000 cells/µL within 48 hours (1 point); (5) endoscopic evidence of pseudomembranous colitis (2 points); and (6) treatment in an intensive care unit (2 points). ॥Denominator is participants in the modified intent-to-treat population with a positive culture. Abbreviations: Bezlo, bezlotoxumab; CDI, Clostridium difficile infection; Hx, history; RT, ribotype.

Figure 2.

Clostridium difficile infection (CDI) recurrence rates by risk factor subgroup (clinical cure population). Unless otherwise specified, each subgroup includes all patients with the risk factor(s) (ie, those with only the specified risk factor[s] and those with the specified risk factor[s] and ≥1 additional risk factor). Abbreviations: CDI Hx, Clostridium difficile infection history in the previous 6 months; CI, confidence interval.

Figure 3.

Kaplan-Meier plot of time to Clostridium difficile infection (CDI) recurrence over 12 weeks of follow-up by high-risk-factor subgroups (modified intent-to-treat population). The start date of CDI recurrence was the first date of the new episode of diarrhea. For subjects who were lost to follow-up prior to a CDI recurrence, time to event was right-censored at the date of the last stool record. Participants who completed the 12-week follow-up period without documented CDI recurrence were censored at the date of the last completed stool record. For participants who failed to achieve a clinical cure for the baseline CDI episode, time to event was right-censored at the date of infusion of study medication (day 1). Abbreviations: Bezlo, bezlotoxumab; CDI, Clostridium difficile infection; CI, confidence interval.