Optimal Treatment for Recurrent Clostridium Difficile (OpTION)

July 7, 2023 updated by: VA Office of Research and Development

CSP #596 - Optimal Treatment for Recurrent Clostridium Difficile Infection

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

549

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Puerto Rico
      • San Juan, Puerto Rico, 00921
        • Terminated
        • VA Caribbean Healthcare System, San Juan, PR
  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85012
        • Recruiting
        • Phoenix VA Health Care System, Phoenix, AZ
        • Contact:
        • Contact:
          • MD
      • Tucson, Arizona, United States, 85723
        • Recruiting
        • Southern Arizona VA Health Care System, Tucson, AZ
        • Contact:
        • Contact:
          • MD
    • Arkansas
      • Little Rock, Arkansas, United States, 72205-5484
        • Recruiting
        • Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR
        • Contact:
        • Contact:
    • California
      • Loma Linda, California, United States, 92357
        • Terminated
        • VA Loma Linda Healthcare System, Loma Linda, CA
      • Long Beach, California, United States, 90822
        • Recruiting
        • VA Long Beach Healthcare System, Long Beach, CA
        • Contact:
      • Palo Alto, California, United States, 94304-1290
        • Terminated
        • VA Palo Alto Health Care System, Palo Alto, CA
      • Sacramento, California, United States, 95655
        • Recruiting
        • VA Northern California Health Care System, Mather, CA
        • Contact:
      • San Diego, California, United States, 92161
        • Terminated
        • VA San Diego Healthcare System, San Diego, CA
      • West Los Angeles, California, United States, 90073
        • Terminated
        • VA Greater Los Angeles Healthcare System, West Los Angeles, CA
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • Rocky Mountain Regional VA Medical Center, Aurora, CO
        • Contact:
    • Florida
      • Bay Pines, Florida, United States, 33744
        • Recruiting
        • Bay Pines VA Healthcare System, Pay Pines, FL
        • Contact:
      • Gainesville, Florida, United States, 32608
        • Recruiting
        • North Florida/South Georgia Veterans Health System, Gainesville, FL
        • Contact:
      • Tampa, Florida, United States, 33612
        • Terminated
        • James A. Haley Veterans' Hospital, Tampa, FL
    • Georgia
      • Decatur, Georgia, United States, 30033
        • Recruiting
        • Atlanta VA Medical and Rehab Center, Decatur, GA
        • Contact:
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Recruiting
        • Jesse Brown VA Medical Center, Chicago, IL
        • Contact:
      • Hines, Illinois, United States, 60141
        • Recruiting
        • Edward Hines Jr. VA Hospital, Hines, IL
        • Contact:
      • Hines, Illinois, United States, 60141-3030
        • Active, not recruiting
        • Edward Hines Jr. VA Hospital, Hines, IL
    • Maryland
      • Baltimore, Maryland, United States, 21202
        • Recruiting
        • Rehabilitation R&D Service, Baltimore, MD
        • Contact:
    • Massachusetts
      • Boston, Massachusetts, United States, 02130
        • Recruiting
        • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
        • Contact:
    • Michigan
      • Ann Arbor, Michigan, United States, 48105
        • Terminated
        • VA Ann Arbor Healthcare System, Ann Arbor, MI
      • Detroit, Michigan, United States, 48201
        • Recruiting
        • John D. Dingell VA Medical Center, Detroit, MI
        • Contact:
    • North Carolina
      • Asheville, North Carolina, United States, 28805
        • Recruiting
        • Asheville VA Medical Center, Asheville, NC
        • Contact:
      • Durham, North Carolina, United States, 27705
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • Recruiting
        • Louis Stokes VA Medical Center, Cleveland, OH
        • Contact:
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
    • Oregon
      • Portland, Oregon, United States, 97239
        • Recruiting
        • VA Portland Health Care System, Portland, OR
        • Contact:
        • Contact:
          • MD
    • Texas
      • Dallas, Texas, United States, 75216
        • Recruiting
        • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
        • Contact:
      • Houston, Texas, United States, 77030
        • Terminated
        • Michael E. DeBakey VA Medical Center, Houston, TX
      • San Antonio, Texas, United States, 78229
        • Terminated
        • South Texas Health Care System, San Antonio, TX
    • Utah
      • Salt Lake City, Utah, United States, 84148
        • Terminated
        • VA Salt Lake City Health Care System, Salt Lake City, UT
    • Washington
      • Seattle, Washington, United States, 98108
        • Terminated
        • VA Puget Sound Health Care System Seattle Division, Seattle, WA
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53295-1000
        • Recruiting
        • Clement J. Zablocki VA Medical Center, Milwaukee, WI
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Fidaxomicin
Standard 10-day fidaxomicin treatment for Clostridium difficile
Drug: Fidaxomicin
200 mg PO twice daily for 10 days
Other: Vancomycin T/P
Standard 10-day vancomycin treatment followed by taper and pulse vancomycin treatment for Clostridium difficile
Drug: Vancomycin with Taper/Pulse
125 mg PO four times daily for 10 days, followed by 125 mg once daily x 7 days, then once every other day x 7 days, then once every 3rd day x 7 days
Other: Vancomycin
Standard 10-day vancomycin treatment for Clostridium difficile
Drug: Vancomycin
125 mg PO for times daily for 10 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Time Frame: Day 59 for all treatment regimens.

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
Day 59 for all treatment regimens.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CDI Composite outcome measure
Time Frame: Day 59 for all treatment regimens.
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.
Day 59 for all treatment regimens.
Diarrhea Composite outcome measure
Time Frame: Day 38 since randomization for vancomycin and fidaxomicin, day 59 since randomization for vancomycin followed by tapering and pulse dose regimen
Sustained clinical response in Diarrhea Composite Outcome (D-COM) at 28 days post end of therapy
Day 38 since randomization for vancomycin and fidaxomicin, day 59 since randomization for vancomycin followed by tapering and pulse dose regimen
Diarrhea Composite outcome measure
Time Frame: Day 90 since randomization
Sustained clinical response in Diarrhea Composite Outcome (D-COM) at 90 days post randomization
Day 90 since randomization
CDI Composite outcome measure
Time Frame: Day 38 since randomization for vancomycin and fidaxomicin, day 59 since randomization for vancomycin followed by tapering and pulse dose regimen
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.
Day 38 since randomization for vancomycin and fidaxomicin, day 59 since randomization for vancomycin followed by tapering and pulse dose regimen
CDI Composite outcome measure
Time Frame: Day 59 since randomization
Sustained clinical response in CDI Composite Outcome (CDI-COM) at 59 days post randomization
Day 59 since randomization
CDI Composite outcome measure
Time Frame: Day 90 since randomization
Sustained clinical response in CDI Composite Outcome (CDI-COM) at 90 days post randomization
Day 90 since randomization
Symptom resolution
Time Frame: Day 10 since randomization
Proportion of subjects with symptom resolution by day 10
Day 10 since randomization
Symptom resolution
Time Frame: Day 10 since randomization
Days from randomization to symptom resolution
Day 10 since randomization
Symptom resolution
Time Frame: Day 90 since randomization
Diarrhea recurrence following initial symptom resolution
Day 90 since randomization
Diarrhea recurrence
Time Frame: Day 90 since randomization
Diarrhea recurrence with confirmation of recurrent CDI following initial symptom resolution
Day 90 since randomization
C.diff Health Related Quality of Life (HRQOL)
Time Frame: Day 90 since randomization
Change in patient reported C.diff Health Related Quality of Life (HRQOL) from baseline (day 0) to day 10
Day 90 since randomization
C.diff Health Related Quality of Life (HRQOL)
Time Frame: Day 90 since randomization
Change in patient reported C.diff Health Related Quality of Life (HRQOL) from baseline (day 0) to day 59
Day 90 since randomization
Sustained clinical response (D-COM)
Time Frame: Day 59 since randomization
Sustained clinical response (D-COM) at day 59 for subgroups (infection with the BI/NAP1/027 strain (yes, no) at study enrollment; etc.)
Day 59 since randomization
Sustained clinical response (CDI-COM)
Time Frame: Day 59 since randomization
Sustained clinical response (CDI-COM) at day 59 for subgroups (infection with the BI/NAP1/027 strain (yes, no) at study enrollment; etc.)
Day 59 since randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Investigators

  • Study Chair: Stuart B. Johnson, MD BA, Edward Hines Jr. VA Hospital, Hines, IL
  • Study Chair: Dale N Gerding, MD, Edward Hines Jr. VA Hospital, Hines, IL

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 21, 2015

Primary Completion (Estimated)

August 31, 2024

Study Completion (Estimated)

August 31, 2024

Study Registration Dates

First Submitted

January 25, 2016

First Submitted That Met QC Criteria

January 25, 2016

First Posted (Estimated)

January 28, 2016

Study Record Updates

Last Update Posted (Actual)

July 10, 2023

Last Update Submitted That Met QC Criteria

July 7, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 596
  • #15-03 (Other Identifier: VA Central IRB)
  • 1613088 (Other Identifier: Hines R&DC)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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