Optimal Treatment for Recurrent Clostridium Difficile

*As a consequence of the COVID-19 pandemic, and after consultation with the appropriate research oversight, regulatory and monitoring entities, screening and enrollment has been placed on temporary administrative hold as of 03/27/2020. When such trial activities resume the clinicaltrials.gov record will be updated accordingly. * Clostridium difficile is the most common cause of healthcare-associated infectious diarrhea among adults in industrialized countries. In addition to diarrhea, C. difficile infection (CDI) may also result in serious complications such as shock, toxic megacolon, colectomy, and death. The Centers for Disease Control and Prevention (CDC) has estimated C. difficile results in 250,000 hospital infections, 14,000 deaths, and $1 billion in excess costs annually. Recurrent CDI is the most challenging clinical dilemma facing clinicians who treat this disease. An estimated 30% of patients who respond to initial treatment with either vancomycin or metronidazole develop recurrent CDI, usually within 1-4 weeks of completing treatment.

The primary objective of this study is to determine whether 1) standard fidaxomicin treatment and 2) standard vancomycin treatment followed by taper and pulse vancomycin treatment are superior to standard vancomycin treatment alone for sustained clinical response at day 59 for all treatments, for participants with either their first or second recurrence of CDI. Veterans presenting with a first or second CDI recurrence will be screened, consented and randomly assigned in a double-blind manner to one of three treatment groups: 1) a 10 day course of oral vancomycin (VAN-TX), 2) a 10 day course of fidaxomicin (FID-TX) or 3) a 31 day course of vancomycin which includes a taper and pulse following daily treatment (VAN-TP/P). Symptom resolution is defined as an improvement or resolution of diarrhea (<3 unformed bowel movements over 24 hours) for 48 consecutive hours compared to the participant's baseline. Recurrence is defined as having diarrhea (>3 loose or semi-formed stools over 24 hours for 48 consecutive hours). A sample size of 546 randomized study participants is required to obtain at least 81% power to detect a 16% absolute difference (expected proportion of 31% in the VAN-TX group) in sustained clinical response (D- COM) proportion 1) between the FID-TX group and the VAN-TX group and 2) between the VAN-TP/P group and VAN-TX group at the 0.05 significance level. It was observed throughout the pilot phase that the original goal of 7 participants per site per year is overestimated. We expect sites will recruit at a more realistic rate of 6 participants (on average) per site per year for sites that will primarily recruit from the main hospital and nearby CBOCS, and 9 participants (on average) per site per year for sites that could partner with independent VAMCs (Independent VAMCs LSI Application will be reviewed and approved by Central IRB) that are close in distance to allow a shared site coordinator (WOC appointed) at an increased funding level. Some sites may recruit more to reach the overall goal. Given revised anticipated recruitment rate and in consideration of sites' variability on start-up dates, different level of recruitment across sites, and logistics on replacement of underperformed sites with backup sites, the study is expected to complete enrollment of 546 participants within 6 years with 90 days of follow-up. This includes 2 years of pilot phase plus transitioning period from pilot phase to full study, and 4 years of full study. There were 6 sites in the pilot phase and will have 24 sites in full phase (including 5 pilot sites and 19 additional sites). This assumes that 30% of Veterans with CDI have a recurrence and 20% of them will enroll in the study.