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Optimal Treatment for Recurrent Clostridium Difficile (OpTION)

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ClinicalTrials.gov Identifier: NCT02667418
Recruitment Status : Recruiting
First Posted : January 28, 2016
Last Update Posted : July 8, 2021
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

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.

Condition or disease Intervention/treatment Phase
Clostridium Difficile Fidaxomicin Vancomycin Drug: Fidaxomicin Drug: Vancomycin with Taper/Pulse Drug: Vancomycin Phase 4

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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 549 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: CSP #596 - Optimal Treatment for Recurrent Clostridium Difficile Infection
Actual Study Start Date : December 21, 2015
Estimated Primary Completion Date : May 31, 2022
Estimated Study Completion Date : May 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Fidaxomicin
Standard 10-day fidaxomicin treatment for Clostridium difficile
Drug: Fidaxomicin
200 mg PO twice daily for 10 days

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

Vancomycin
Standard 10-day vancomycin treatment for Clostridium difficile
Drug: Vancomycin
125 mg PO for times daily for 10 days




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. 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

  3. Diarrhea Composite outcome measure [ Time Frame: Day 90 since randomization ]
    Sustained clinical response in Diarrhea Composite Outcome (D-COM) at 90 days post randomization

  4. 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.

  5. CDI Composite outcome measure [ Time Frame: Day 59 since randomization ]
    Sustained clinical response in CDI Composite Outcome (CDI-COM) at 59 days post randomization

  6. CDI Composite outcome measure [ Time Frame: Day 90 since randomization ]
    Sustained clinical response in CDI Composite Outcome (CDI-COM) at 90 days post randomization

  7. Symptom resolution [ Time Frame: Day 10 since randomization ]
    Proportion of subjects with symptom resolution by day 10

  8. Symptom resolution [ Time Frame: Day 10 since randomization ]
    Days from randomization to symptom resolution

  9. Symptom resolution [ Time Frame: Day 90 since randomization ]
    Diarrhea recurrence following initial symptom resolution

  10. Diarrhea recurrence [ Time Frame: Day 90 since randomization ]
    Diarrhea recurrence with confirmation of recurrent CDI following initial symptom resolution

  11. 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

  12. 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

  13. 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.)

  14. 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.)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02667418


Contacts
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Contact: Michelle Johnson (708) 202-8387 ext 27001 Michelle.Johnson5@va.gov
Contact: Xue Li, PhD (708) 202-4992 Xue.li@va.gov

Locations
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Sponsors and Collaborators
VA Office of Research and Development
Investigators
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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
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT02667418    
Other Study ID Numbers: 596
#15-03 ( Other Identifier: VA Central IRB )
First Posted: January 28, 2016    Key Record Dates
Last Update Posted: July 8, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by VA Office of Research and Development:
Clostridium
Difficile
Fidaxomicin
Vancomycin
Recurrent
Pulse
Taper
Additional relevant MeSH terms:
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Vancomycin
Fidaxomicin
Anti-Bacterial Agents
Anti-Infective Agents