Optimal Treatment for Recurrent Clostridium Difficile
Optimal Treatment for Recurrent Clostridium Difficile
The purpose of this study is to determine whether fidaxomicin and vancomycin followed by
 taper and pulse vancomycin treatment are superior to standard vancomycin treatment for the
 treatment of recurrent Clostridium difficile infection.
*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. * Abstract 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 equally 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 549 randomized study
 participants is required to obtain 91% global power to detect a 16% absolute difference
 (expected proportion of 31% in the VAN-TX group) in sustained clinical response (D- COM)
 proportion for at least one comparison (VAN-TP/P vs. VAN-TX, FID-TX vs. VAN-TX) at the family
 wised error rate (FWER) 0.05 level. The marginal probability (disjunctive power) of detecting
 16% absolute difference for each comparison is 81%. The expected withdrawal rate prior to day
 59 (prior outcome assessment) is estimated to be 10%. If both FID-TX and VAN-TP/P are found
 to be superior to VAN-TX, then the non-inferiority of VAN-TP/P to FID-TX will be assessed.

 With the assumption that sites recruit 6 participants (site average) per year for sites
 primarily recruiting from the main hospital and nearby CBOCS, and 9 participants (site
 average) 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, the study is
 expected to complete enrollment of 549 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
 units (26 sites) in full phase (including 5 pilot sites and 21 additional sites). Sites that
 are significantly below the recruitment target for an extensive period may be considered for
 termination. The recruitment timeline and the number of sites will be re-evaluated based on
 the actual recruitment rate, the number of sites still recruiting, whether replacement or
 additional sites will be added, the study time period on administrative recruitment hold due
 to COVID-19 pandemic, and available funding resources.
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)