Optimal Treatment for Recurrent Clostridium Difficile

Phase 4

Terminated

Conditions: Difficile
Fidaxomicin
Vancomycin
Clostridium

Interventions: Drug: Fidaxomicin
Drug: Vancomycin
Drug: Vancomycin with Taper/Pulse

Registration Number: NCT02667418

Lead Sponsor: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 308

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fidaxomicin	Fidaxomicin	Standard 10-day fidaxomicin treatment for Clostridium difficile
Vancomycin	Vancomycin	Standard 10-day vancomycin treatment for Clostridium difficile
Vancomycin T/P	Vancomycin with Taper/Pulse	Standard 10-day vancomycin treatment followed by taper and pulse vancomycin treatment for Clostridium difficile

Primary Outcome Measures

Name	Time	Method
Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	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

Name	Time	Method
Sustained Diarrhea Composite Outcome (D-COM) at 28 Days Post End of Therapy	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.
Clostridium Difficile Infection Composite Outcome (CDI-COM)	Day 59 post randomization	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).
Symptom Resolution	Day 10 since randomization	The percentage of participants who had symptom resolution by Day 10 post randomization
CDI Recurrence	Day 59 since randomization	CDI recurrence following initial symptom resolution
Diarrhea Recurrence	Day 59 since randomization	Diarrhea recurrence with confirmation of recurrent CDI following initial symptom resolution
C.Diff Health Related Quality of Life (HRQOL)	day 0- day 59	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.
Sustained Clinical Response (D-COM) BI/NAP1/027 Strain as "Yes"	Day 59 since randomization	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.
Sustained Clinical Response (D-COM) With the BI/NAP1/027 Strain no	Day 59 since randomization	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.
Sustained Diarrhea Composite Outcome (D-COM) at 90 Days After Randomization	90 Days After Randomization	Sustained Diarrhea Composite Outcome (D-COM) at 90 days after Randomization - Secondary Analyses of Primary Outcome

Trial Locations

Locations (32): Phoenix VA Health Care System, Phoenix, AZ
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Phoenix, Arizona, United States
Southern Arizona VA Health Care System, Tucson, AZ
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Tucson, Arizona, United States
Central Arkansas Veterans Healthcare System, Little Rock, AR
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Little Rock, Arkansas, United States
VA Loma Linda Healthcare System, Loma Linda, CA
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Loma Linda, California, United States
VA Long Beach Healthcare System, Long Beach, CA
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Long Beach, California, United States
VA Palo Alto Health Care System, Palo Alto, CA
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Palo Alto, California, United States
VA Northern California Health Care System, Mather, CA
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Sacramento, California, United States
VA San Diego Healthcare System, San Diego, CA
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San Diego, California, United States
VA Greater Los Angeles Healthcare System, West Los Angeles, CA
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West Los Angeles, California, United States
Rocky Mountain Regional VA Medical Center, Aurora, CO
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Aurora, Colorado, United States
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Phoenix VA Health Care System, Phoenix, AZ
🇺🇸Phoenix, Arizona, United States