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.

Optimal Treatment for Recurrent Clostridium Difficile

Clostridium

Difficile

Fidaxomicin

Vancomycin

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 459 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 4 participants (site average) per year for sites
      primarily recruiting from the main hospital and nearby CBOCS, and 6 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 459 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.

Vancomycin with Taper/Pulse

CSP #596 - Optimal Treatment for Recurrent Clostridium Difficile Infection

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

CDI Composite Outcome Measure (CDI-COM) is sustained clinical response without recurrent CDI (defined as diarrhea plus confirmation of toxigenic C. difficile or its toxins in stool) as measured at study day 59 for all three treatment regimens. Sustained response will be defined using the same composite endpoint criteria as were used in the D-COM outcome but without recurrent CDI on or before day 59.

Sustained clinical response in Diarrhea Composite Outcome (D-COM) at 28 days post end of therapy

Sustained clinical response in Diarrhea Composite Outcome (D-COM) at 90 days post randomization

Sustained clinical response in CDI Composite Outcome (CDI-COM) at 28 days post end of therapy. Sustained response in CDI-COM is defined using the same composite endpoint criteria as was used in the D-COM composite outcome (primary outcome) but with confirmation of no CDI recurrence by a negative C. difficile stool assay test.

Sustained clinical response in CDI Composite Outcome (CDI-COM) at 59 days post randomization

Sustained clinical response in CDI Composite Outcome (CDI-COM) at 90 days post randomization

Proportion of subjects with symptom resolution by day 10

Days from randomization to symptom resolution

Diarrhea recurrence following initial symptom resolution

Diarrhea recurrence with confirmation of recurrent CDI following initial symptom resolution

Change in patient reported C.diff Health Related Quality of Life (HRQOL) from baseline (day 0) to day 10

Change in patient reported C.diff Health Related Quality of Life (HRQOL) from baseline (day 0) to day 59

Sustained clinical response (D-COM) at day 59 for subgroups (infection with the BI/NAP1/027 strain (yes, no) at study enrollment; etc.)

Sustained clinical response (CDI-COM) at day 59 for subgroups (infection with the BI/NAP1/027 strain (yes, no) at study enrollment; etc.)

Standard 10-day fidaxomicin treatment for Clostridium difficile

Standard 10-day vancomycin treatment followed by taper and pulse vancomycin treatment for Clostridium difficile

Standard 10-day vancomycin treatment for Clostridium difficile

Phoenix VA Health Care System, Phoenix, AZ

Southern Arizona VA Health Care System, Tucson, AZ

Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR

Optimal Treatment for Recurrent Clostridium Difficile

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Not accepting

Trial Timing

What is this trial about?

What are the participation requirements?