Clinical trial NCT02667418: Optimal Treatment for Recurrent Clostridium Difficile
Official title: CSP #596 - Optimal Treatment for Recurrent Clostridium Difficile Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Clostridium
Difficile
Fidaxomicin
Vancomycin
Keywords: Clostridium
Difficile
Fidaxomicin
Vancomycin
Recurrent
Pulse
Taper
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2016-01-28
Enrollment: 308
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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)
* Patients with an active diagnosis of COVID-19 will be excluded from the study, but patients who have recovered (per current CDC guidance on discontinuation of transmission-based precautions) can be included in the study.

Primary outcomes:
measure: Determine symptom resolution during treatment without any of the following: diarrhea recurrence; other non-fatal clinical events including severe abdominal pain, toxic megacolon, and colectomy; and death.
timeFrame: Day 59 for all treatment regimens.
Secondary outcomes:
measure: CDI Composite outcome measure
timeFrame: Day 59 for all treatment regimens.
measure: Diarrhea Composite outcome measure
timeFrame: Day 38 since randomization for vancomycin and fidaxomicin, day 59 since randomization for vancomycin followed by tapering and pulse dose regimen
measure: Diarrhea Composite outcome measure
timeFrame: Day 90 since randomization
measure: CDI Composite outcome measure
timeFrame: Day 38 since randomization for vancomycin and fidaxomicin, day 59 since randomization for vancomycin followed by tapering and pulse dose regimen
measure: CDI Composite outcome measure
timeFrame: Day 59 since randomization
measure: CDI Composite outcome measure
timeFrame: Day 90 since randomization
measure: Symptom resolution
timeFrame: Day 10 since randomization
measure: Symptom resolution
timeFrame: Day 10 since randomization
measure: Symptom resolution
timeFrame: Day 90 since randomization
measure: Diarrhea recurrence
timeFrame: Day 90 since randomization
measure: C.diff Health Related Quality of Life (HRQOL)
timeFrame: Day 90 since randomization
measure: C.diff Health Related Quality of Life (HRQOL)
timeFrame: Day 90 since randomization
measure: Sustained clinical response (D-COM)
timeFrame: Day 59 since randomization
measure: Sustained clinical response (CDI-COM)
timeFrame: Day 59 since randomization
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix VA Health Care System, Phoenix, AZ
state: Arizona
city: Tucson
country: United States
facility: Southern Arizona VA Health Care System, Tucson, AZ
state: Arizona
city: Little Rock
country: United States
facility: Central Arkansas Veterans Healthcare System, Little Rock, AR
state: Arkansas
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System, Loma Linda, CA
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System, Long Beach, CA
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
city: Sacramento
country: United States
facility: VA Northern California Health Care System, Mather, CA
state: California
city: San Diego
country: United States
facility: VA San Diego Healthcare System, San Diego, CA
state: California
city: West Los Angeles
country: United States
facility: VA Greater Los Angeles Healthcare System, West Los Angeles, CA
state: California
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center, Aurora, CO
state: Colorado
city: Bay Pines
country: United States
facility: Bay Pines VA Healthcare System, Pay Pines, FL
state: Florida
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System, Gainesville, FL
state: Florida
city: Tampa
country: United States
facility: James A. Haley Veterans' Hospital, Tampa, FL
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur, GA
state: Georgia
city: Chicago
country: United States
facility: Jesse Brown VA Medical Center, Chicago, IL
state: Illinois
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: Baltimore
country: United States
facility: Rehabilitation R&D Service, Baltimore, MD
state: Maryland
city: Boston
country: United States
facility: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
state: Massachusetts
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System, Ann Arbor, MI
state: Michigan
city: Detroit
country: United States
facility: John D. Dingell VA Medical Center, Detroit, MI
state: Michigan
city: Asheville
country: United States
facility: Asheville VA Medical Center, Asheville, NC
state: North Carolina
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
city: Cleveland
country: United States
facility: Louis Stokes VA Medical Center, Cleveland, OH
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma City VA Medical Center, Oklahoma City, OK
state: Oklahoma
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: San Antonio
country: United States
facility: South Texas Health Care System, San Antonio, TX
state: Texas
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
city: Seattle
country: United States
facility: VA Puget Sound Health Care System Seattle Division, Seattle, WA
state: Washington
city: Milwaukee
country: United States
facility: Clement J. Zablocki VA Medical Center, Milwaukee, WI
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: VA Caribbean Healthcare System, San Juan, PR
Study officials:
affiliation: Edward Hines Jr. VA Hospital, Hines, IL
name: Stuart B. Johnson, MD BA
role: STUDY_CHAIR
affiliation: Edward Hines Jr. VA Hospital, Hines, IL
name: Dale N Gerding, MD
role: STUDY_CHAIR
References:
citation: Johnson S, Gerding DN, Li X, Reda DJ, Donskey CJ, Gupta K, Goetz MB, Climo MW, Gordin FM, Ringer R, Johnson N, Johnson M, Calais LA, Goldberg AM, Ge L, Haegerich T. Defining optimal treatment for recurrent Clostridioides difficile infection (OpTION study): A randomized, double-blind comparison of three antibiotic regimens for patients with a first or second recurrence. Contemp Clin Trials. 2022 May;116:106756. doi: 10.1016/j.cct.2022.106756. Epub 2022 Apr 7.