Optimal Treatment for Recurrent Clostridium Difficile

Study Overview
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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.

Official Title
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CSP #596 - Optimal Treatment for Recurrent Clostridium Difficile Infection

Conditions
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Clostridium, Difficile, Fidaxomicin, Vancomycin

Intervention / Treatment
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* Drug: Fidaxomicin
* Drug: Vancomycin with Taper/Pulse
* Drug: Vancomycin


Participation Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Fidaxomicin<br>Standard 10-day fidaxomicin treatment for Clostridium difficile | Drug: Fidaxomicin<br>* 200 mg PO twice daily for 10 days<br>|
| Other: Vancomycin T/P<br>Standard 10-day vancomycin treatment followed by taper and pulse vancomycin treatment for Clostridium difficile | Drug: Vancomycin with Taper/Pulse<br>* 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<br>|
| Other: Vancomycin<br>Standard 10-day vancomycin treatment for Clostridium difficile | Drug: Vancomycin<br>* 125 mg PO for times daily for 10 days<br>|

What is the study measuring?
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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. | 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 |
| --- | --- | --- |
| CDI Composite outcome measure | 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 | 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 | Sustained clinical response in Diarrhea Composite Outcome (D-COM) at 90 days post randomization | Day 90 since randomization | 
| CDI Composite outcome measure | 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 | Sustained clinical response in CDI Composite Outcome (CDI-COM) at 59 days post randomization | Day 59 since randomization | 
| CDI Composite outcome measure | Sustained clinical response in CDI Composite Outcome (CDI-COM) at 90 days post randomization | Day 90 since randomization | 
| Symptom resolution | Proportion of subjects with symptom resolution by day 10 | Day 10 since randomization | 
| Symptom resolution | Days from randomization to symptom resolution | Day 10 since randomization | 
| Symptom resolution | Diarrhea 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 | 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 59 | Day 90 since randomization | 
| Sustained clinical response (D-COM) | 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) | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clostridium, Difficile, Fidaxomicin, Vancomycin, Recurrent, Pulse, Taper