Optimal Treatment for Recurrent Clostridium Difficile (OpTION)

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: Terminated
• Conditions: Vancomycin; Clostridium; Difficile; Fidaxomicin
• Intervention / Treatment: Drug: Fidaxomicin; Drug: Vancomycin with Taper/Pulse; Drug: Vancomycin

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 (Actual): 308
• Phase: Phase 4

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00921
    • VA Caribbean Healthcare System, San Juan, PR
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Phoenix VA Health Care System, Phoenix, AZ
    • Tucson, Arizona, United States, 85723-0001
      • Southern Arizona VA Health Care System, Tucson, AZ
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Central Arkansas Veterans Healthcare System, Little Rock, AR
  • California
    • Loma Linda, California, United States, 92357
      • VA Loma Linda Healthcare System, Loma Linda, CA
    • Long Beach, California, United States, 90822
      • VA Long Beach Healthcare System, Long Beach, CA
    • Palo Alto, California, United States, 94304-1290
      • VA Palo Alto Health Care System, Palo Alto, CA
    • Sacramento, California, United States, 95655-4200
      • VA Northern California Health Care System, Mather, CA
    • San Diego, California, United States, 92161
      • VA San Diego Healthcare System, San Diego, CA
    • West Los Angeles, California, United States, 90073
      • VA Greater Los Angeles Healthcare System, West Los Angeles, CA
  • Colorado
    • Aurora, Colorado, United States, 80045-7211
      • Rocky Mountain Regional VA Medical Center, Aurora, CO
  • Florida
    • Bay Pines, Florida, United States, 33744-0000
      • Bay Pines VA Healthcare System, Pay Pines, FL
    • Gainesville, Florida, United States, 32608-1135
      • North Florida/South Georgia Veterans Health System, Gainesville, FL
    • Tampa, Florida, United States, 33612
      • James A. Haley Veterans' Hospital, Tampa, FL
  • Georgia
    • Decatur, Georgia, United States, 30033-4004
      • Atlanta VA Medical and Rehab Center, Decatur, GA
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Jesse Brown VA Medical Center, Chicago, IL
    • Hines, Illinois, United States, 60141
      • Edward Hines Jr. VA Hospital, Hines, IL
    • Hines, Illinois, United States, 60141-3030
      • Edward Hines Jr. VA Hospital, Hines, IL
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Rehabilitation R&D Service, Baltimore, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02130-4817
      • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • VA Ann Arbor Healthcare System, Ann Arbor, MI
    • Detroit, Michigan, United States, 48201-1916
      • John D. Dingell VA Medical Center, Detroit, MI
  • North Carolina
    • Asheville, North Carolina, United States, 28805-2576
      • Asheville VA Medical Center, Asheville, NC
    • Durham, North Carolina, United States, 27705-3875
      • Durham VA Medical Center, Durham, NC
  • Ohio
    • Cleveland, Ohio, United States, 44106-1702
      • Louis Stokes VA Medical Center, Cleveland, OH
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104-5007
      • Oklahoma City VA Medical Center, Oklahoma City, OK
  • Oregon
    • Portland, Oregon, United States, 97207-2964
      • VA Portland Health Care System, Portland, OR
  • Texas
    • Dallas, Texas, United States, 75216-7167
      • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center, Houston, TX
    • San Antonio, Texas, United States, 78229
      • South Texas Health Care System, San Antonio, TX
  • Utah
    • Salt Lake City, Utah, United States, 84148
      • VA Salt Lake City Health Care System, Salt Lake City, UT
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System Seattle Division, Seattle, WA
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53295-0001
      • Clement J. Zablocki VA Medical Center, Milwaukee, WI

Participation Criteria

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

How is the study designed?

Design Details

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

Number of Arms

3

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
Number of Participants With Sustained Clinical Response as Measured at Study 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): 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	Day 59 for all treatment regimens.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sustained Diarrhea Composite Outcome (D-COM) at 28 Days Post End of Therapy	Sustained Diarrhea Composite Outcome (D-COM) at 28 days Post End of Therapy- Secondary Analyses of Primary Outcome. Sustained clinical response without recurrent CDI (CDI-COM) at 28 days post end of therapy for all three treatment regimens. Sustained clinical response was defined using the same criteria as previously stated except that the endpoint will be 28 days after the last dose of treatment drug for each treatment arm (day 38 for vancomycin and fidaxomicin, and day 59 for vancomycin taper/pulse).Sustained clinical response is a composite endpoint defined as symptom resolution during treatment without diarrhea recurrence, mortality or other important clinical outcomes at any time during the follow-up period. Those participants failing to meet the criteria of symptom resolution (diarrhea resolution) by the end of the active treatment (day 10 for all groups), or who experience a recurrence during the follow-up period, will be considered study treatment failures.	28 Days Post End of Therapy
Clostridium Difficile Infection Composite Outcome (CDI-COM)	Clostridium difficile Infection Composite Outcome (CDI-COM) at day 59 post randomization. Sustained response in CDI-COM is defined using the same composite endpoint criteria as was used in the D-COM composite outcome but with confirmation of no CDI recurrence by a negative C. difficile stool assay test (i.e., proportion of subjects who achieve symptom resolution by day 10 without recurrent CDI, without non-fatal clinical events, and without death).	Day 59 post randomization
Symptom Resolution	The percentage of participants who had symptom resolution by Day 10 post randomization	Day 10 since randomization
CDI Recurrence	CDI recurrence following initial symptom resolution	Day 90 since randomization
Diarrhea Recurrence	Diarrhea recurrence with confirmation of recurrent CDI following initial symptom resolution	Day 90 since randomization
C.Diff Health Related Quality of Life (HRQOL)	Change in patient reported C.diff Health Related Quality of Life (HRQOL) from baseline (day 0) to day 10. The HRQOL is measured with patient self-reported 32-item questionnaire. The summary measure, CDiff32-QOL, is the total score that sums over 32 individual items with each item rated on a 5-point Likert scale and then transformed to a 100-point scale with higher score indicating better C.diff Health Related QOL in general. The full scale of the HRQOL: 1-5 on a 5-point Likert scale and 0-100 on the 100-point scale; the minimum: 0 on the 100-point scale and maximum value: 100 on the 100-point scale. The summary measure (32 items) range on the 100-point scale: 0-3200.	Day 10 since randomization
C.Diff Health Related Quality of Life (HRQOL)	Change in patient reported C.diff Health Related Quality of Life (HRQOL) from baseline day 0 to day 59. The HRQOL is measured with patient self-reported 32-item questionnaire. The summary measure, CDiff32-QOL, is the total score that sums over 32 individual items with each item rated on a 5-point Likert scale and then transformed to a 100-point scale with higher score indicating better C.diff Health Related QOL in general. The full scale of the HRQOL: 1-5 on a 5-point Likert scale and 0-100 on the 100-point scale; the minimum: 0 on the 100-point scale and maximum value: 100 on the 100-point scale. The summary measure (32 items) range on the 100-point scale: 0-3200.	day 0- day 59
Sustained Clinical Response (D-COM) BI/NAP1/027 Strain as "Yes"	Sustained clinical response (D-COM) at day 59 for subgroups (infection with the BI/NAP1/027 strain (yes) at study enrollment; etc.). The sliced analysis was used to break down the subgroup factors into different sub-levels and then to explore the differences between treatment group (VAN-TP and FDX) and VAN control group at each level.	Day 59 since randomization
Diarrhea Recurrence	Diarrhea recurrence with confirmation of recurrent CDI following initial symptom resolution. Diarrhea recurrence and diarrhea recurrence with confirmation of recurrent CDI following initial symptom resolution. Diarrhea (>3 loose or semi-formed stools over 24 hours) over 48 consecutive hours in participants who achieved initial symptom resolution will be recorded separately from sustained clinical response as will confirmed CDI recurrence.	Day 38 since randomization
Diarrhea Recurrence	Diarrhea recurrence with confirmation of recurrent CDI following initial symptom resolution	Day 59 since randomization
CDI Recurrence	CDI recurrence following initial symptom resolution	Day 38 since randomization
CDI Recurrence	CDI recurrence following initial symptom resolution	Day 59 since randomization
Sustained Clinical Response (D-COM) With the BI/NAP1/027 Strain no	Sustained clinical response (D-COM) at day 59 for subgroups (infection with the BI/NAP1/027 strain (no) at study enrollment; etc.). The sliced analysis was used to break down the subgroup factors into different sub-levels and then to explore the differences between therapy group (VAN-TP and FDX) and VAN control group at each level.	Day 59 since randomization
Sustained Diarrhea Composite Outcome (D-COM) at 90 Days After Randomization	Sustained Diarrhea Composite Outcome (D-COM) at 90 days after Randomization - Secondary Analyses of Primary Outcome	90 Days After Randomization

Collaborators and Investigators

• 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

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2016
• Primary Completion (Actual): August 7, 2024
• Study Completion (Actual): 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 (Estimated): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 11, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Vancomycin; Recurrent; Pulse; Fidaxomicin; Clostridium; Difficile; Taper
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pathological Conditions, Signs and Symptoms; Recurrence; Peptides; Amino Acids, Peptides, and Proteins; Organic Chemicals; Circulatory and Respiratory Physiological Phenomena; Carbohydrates; Polycyclic Compounds; Macrolides; Lactones; Glycoconjugates; Macrocyclic Compounds; Glycopeptides; Polyketides; Hemodynamics; Cardiovascular Physiological Phenomena; Fidaxomicin; Vancomycin; Pulse
• 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