Optimal Treatment for Recurrent Clostridium Difficile

NCT ID: NCT02667418

Last Updated: 2025-11-12

Study Results

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE4

Total Enrollment

308 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-12-21

Study Completion Date

2024-08-31

Brief Summary

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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

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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.

Conditions

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Clostridium Difficile Fidaxomicin Vancomycin

Keywords

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Clostridium Difficile Fidaxomicin Vancomycin Recurrent Pulse Taper

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Fidaxomicin

Standard 10-day fidaxomicin treatment for Clostridium difficile

Group Type OTHER

Fidaxomicin

Intervention Type DRUG

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

Group Type OTHER

Vancomycin with Taper/Pulse

Intervention Type DRUG

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

Group Type OTHER

Vancomycin

Intervention Type DRUG

125 mg PO for times daily for 10 days

Interventions

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Fidaxomicin

200 mg PO twice daily for 10 days

Intervention Type 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

Intervention Type DRUG

Vancomycin

125 mg PO for times daily for 10 days

Intervention Type DRUG

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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VA Office of Research and Development

FED

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Stuart B. Johnson, MD BA

Role: STUDY_CHAIR

Edward Hines Jr. VA Hospital, Hines, IL

Dale N Gerding, MD

Role: STUDY_CHAIR

Edward Hines Jr. VA Hospital, Hines, IL

Curtis J. Donskey, MD

Role: STUDY_CHAIR

Louis Stokes Cleveland DVA Medical Center

Locations

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Phoenix VA Health Care System, Phoenix, AZ

Phoenix, Arizona, United States

Site Status

Southern Arizona VA Health Care System, Tucson, AZ

Tucson, Arizona, United States

Site Status

Central Arkansas Veterans Healthcare System, Little Rock, AR

Little Rock, Arkansas, United States

Site Status

VA Loma Linda Healthcare System, Loma Linda, CA

Loma Linda, California, United States

Site Status

VA Long Beach Healthcare System, Long Beach, CA

Long Beach, California, United States

Site Status

VA Palo Alto Health Care System, Palo Alto, CA

Palo Alto, California, United States

Site Status

VA Northern California Health Care System, Mather, CA

Sacramento, California, United States

Site Status

VA San Diego Healthcare System, San Diego, CA

San Diego, California, United States

Site Status

VA Greater Los Angeles Healthcare System, West Los Angeles, CA

West Los Angeles, California, United States

Site Status

Rocky Mountain Regional VA Medical Center, Aurora, CO

Aurora, Colorado, United States

Site Status

Bay Pines VA Healthcare System, Pay Pines, FL

Bay Pines, Florida, United States

Site Status

North Florida/South Georgia Veterans Health System, Gainesville, FL

Gainesville, Florida, United States

Site Status

James A. Haley Veterans' Hospital, Tampa, FL

Tampa, Florida, United States

Site Status

Atlanta VA Medical and Rehab Center, Decatur, GA

Decatur, Georgia, United States

Site Status

Jesse Brown VA Medical Center, Chicago, IL

Chicago, Illinois, United States

Site Status

Edward Hines Jr. VA Hospital, Hines, IL

Hines, Illinois, United States

Site Status

Edward Hines Jr. VA Hospital, Hines, IL

Hines, Illinois, United States

Site Status

Rehabilitation R&D Service, Baltimore, MD

Baltimore, Maryland, United States

Site Status

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Boston, Massachusetts, United States

Site Status

VA Ann Arbor Healthcare System, Ann Arbor, MI

Ann Arbor, Michigan, United States

Site Status

John D. Dingell VA Medical Center, Detroit, MI

Detroit, Michigan, United States

Site Status

Asheville VA Medical Center, Asheville, NC

Asheville, North Carolina, United States

Site Status

Durham VA Medical Center, Durham, NC

Durham, North Carolina, United States

Site Status

Louis Stokes VA Medical Center, Cleveland, OH

Cleveland, Ohio, United States

Site Status

Oklahoma City VA Medical Center, Oklahoma City, OK

Oklahoma City, Oklahoma, United States

Site Status

VA Portland Health Care System, Portland, OR

Portland, Oregon, United States

Site Status

VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Dallas, Texas, United States

Site Status

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, United States

Site Status

South Texas Health Care System, San Antonio, TX

San Antonio, Texas, United States

Site Status

VA Salt Lake City Health Care System, Salt Lake City, UT

Salt Lake City, Utah, United States

Site Status

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Seattle, Washington, United States

Site Status

Clement J. Zablocki VA Medical Center, Milwaukee, WI

Milwaukee, Wisconsin, United States

Site Status

VA Caribbean Healthcare System, San Juan, PR

San Juan, , Puerto Rico

Site Status

Countries

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United States Puerto Rico

References

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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.

Reference Type BACKGROUND
PMID: 35398532 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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#15-03

Identifier Type: OTHER

Identifier Source: secondary_id

1613088

Identifier Type: OTHER

Identifier Source: secondary_id

596

Identifier Type: -

Identifier Source: org_study_id