Optimal Treatment for Recurrent Clostridium Difficile

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.

Inclusion Criteria:

- Informed consent obtained and signed

- Age > 18

- If female, participant must not be pregnant or nursing

- Negative pregnancy test required for females <61 years of age or without prior
hysterectomy

- 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

- Prior infusion of bezlotoxumab within the previous 6 months

- 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)