CSP #596, Optimal Treatment for Recurrent Clostridium Difficile (OpTION)

The Primary outcome will be sustained clinical response as measured at study day 59 for all treatment regimens. Sustained clinical response is a composite outcome that includes symptom resolution during treatment without any of the following (as assessed on day 59):

1. Diarrhea recurrence
2. Other non-fatal clinical events including severe abdominal pain, toxic megacolon (where diarrhea ceases but is not a beneficial outcome), and colectomy
3. Death

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.

Inclusion Criteria:

• Informed consent obtained and signed
• Age >18
• If female, participant must not be pregnant or nursing
• Negative pregnancy test required for females of child bearing age
• Confirmed current diagnosis of CDI, determined by having
• >3 loose or semi-formed stools for participants over 24 hours AND positive stool assay for C. difficile
• EIA positive for toxin A/B; or Cytotoxin assay; or Nucleic Acid Amplification Test (NAAT, PCR or LAMP) based detection of toxigenic C. difficile
• Current episode represents the first recurrent episode of CDI within 3 months of the primary CDI episode in a patient who has not had CDI in the 3 months prior to the primary episode OR a second recurrent CDI episode occurring within 3 months of the first recurrent episode, as defined above
• At least one of the previous CDI episodes must have been confirmed by a stool assay for C. difficile

Exclusion Criteria:

• Inability to provide informed consent
• Inability to take oral capsules
• Receipt of >72 hours of antibiotics considered effective in the treatment of CDI, including:
  • metronidazole
  • vancomycin
  • fidaxomicin
  • nitazoxanide
  • rifaximin
• Known presence of fulminant CDI, including hypotension, severe ileus or GI obstruction or incipient toxic megacolon
• Receipt of more than a single course of oral vancomycin, fidaxomicin, or a vancomycin tapering regimen since the primary episode of CDI as defined above
• Known allergy to vancomycin or fidaxomicin
• Acute or chronic diarrhea due to inflammatory bowel disease or other cause (e.g., presence of an ileostomy or colostomy) that would confound evaluation of response to CDI treatment
• Anticipation of need for long term systemic antibiotic treatment (beyond 7 days)

Local Site Investigator:

Dr. Jessica Johnson, MD
x1236

Study Coordinator:

Craig High
x4620
Craig.High@va.gov