Vancomycin Taper to Prevent Recurrent Clostridioides Difficile (TAPER-V2)

McGill University

Status and phase: Begins enrollment in 3 months; Phase 3

Conditions: Clostridia Difficile Colitis

Treatments: Drug: Vancomycin capsule; Drug: Fidaxomicin

Study type: Interventional

Funder types: Other

Identifiers

NCT07328971

2026-12121

Details and patient eligibility

About

Indirect evidence from network meta-analyses of randomized controlled trials (RCTs) suggest that a pulse and taper (P-T) of vancomycin may be non-inferior to 10-days of fidaxomicin for the prevention of recurrent Clostridioides difficile infections (rCDI). The aim of this trial is:

1) For first episodes and first recurrences of CDI, to test whether a vancomycin P-T is non-inferior to 10-days of fidaxomicin for the prevention of rCDI at 56 days

Full description

C. difficile is a gram positive spore-forming anaerobic bacterium that can cause severe diarrhea through colitis. While the incidence of CDI is decreasing in Canada it remains a major cause of both nosocomial and community-acquired diarrhea. The annual incidence of CDI in Canada is 16,000 cases with 1,300 (8.1%) associated deaths. Estimates suggest that CDI is associated with annual economic losses of ~$150 million in Canada and that 23% of these losses are attributable to recurrent cases. Despite appropriate treatment, approximately 20-30% of CDI cases experience a recurrence (rCDI) and recurrent cases are substantially more costly and deadly. Fidaxomicin reduces the absolute recurrence rate of CDI by ~10% relative to 10 days of vancomycin; however, cost and availability prohibit widespread use. At the current price in Canada, fidaxomicin is not cost-effective. Thus, rCDI is associated with significant morbidity, mortality, and economic cost, and prevention is a substantially unmet clinical need.

International CDI guidelines conflict on the recommended treatments for first episodes and first recurrences. The IDSA and ESCMID favor fidaxomicin for both, the ACG recommends fidaxomicin or vancomycin (P-T for first recurrences) for both, whereas the Association of Medical Microbiology and Infectious Disease (AMMI) Canada favors vancomycin for both. These heterogeneous guidelines are mirrored by significant global practice heterogeneity in the use of fidaxomicin or oral vancomycin (10-14 days or as a P-T) for CDI. Since the publication of these guidelines, the TAPER-V trial (NCT04138706) found a 99.0% probability of superiority of a 4-week vancomycin P-T vs. 14 days of vancomycin for first CDI episodes and recurrences for the rCDI outcome at 38 days. Incorporating TAPER-V into a network meta-analysis of RCTs of treatments for first episodes and recurrences revealed that for the prevention of rCDI at day 38, vancomycin P-T was not significantly different from 10 days of fidaxomicin (Adjusted relative risk=0.73, favouring vancomycin P-T, 95% Confidence Interval (95%CI)=0.33, 1.61). However, only indirect evidence was available for this comparison because vancomycin P-T and fidaxomicin have never been compared head-to-head in an RCT.

Although the probability of superiority for vancomycin P-T vs. 14 days of vancomycin in TAPER-V for rCDI was 99.0% at 38 days, this probability fell to 73.8% at 56 days (i.e., the IDSA timeframe for rCDI), and 62.1% at 90 days. All the available RCT evidence for 10 days of fidaxomicin in the prevention of rCDI is within a 40 day timeframe. Thus, it is unknown whether the benefit of fidaxomicin also wanes over time.

By contrast to fidaxomicin, vancomycin P-T has greater worldwide availability and markedly reduced cost. If it is non-inferior or superior to fidaxomicin in terms of preventing rCDI over the long term (e.g., at least 56 days), it will represent a very important addition to international treatment algorithms.

To determine whether vancomycin P-T is an alternative to fidaxomicin, the investigators propose a non-inferiority RCT comparing vancomycin P-T to 10 days of fidaxomicin for the treatment of first episodes and first recurrences of CDI. Indeed, 68.2% of respondents to a recent clinician survey on CDI supported a trial on this comparison. The proposed trial will directly inform clinical practice on the potential of vancomycin P-T as a non-inferior and a lower-cost first-line therapy for CDI. This trial will also be the first to provide data on the longer term rCDI rate (beyond days 38-40) for fidaxomicin.

Enrollment: 500 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Inpatient or outpatient adults (≥18 years old) treated at the participating institutions.
• First episode or first recurrence of CDI (i.e., second episode within 56 days) defined by a positive C. difficile assay (including PCR toxin gene detection, toxin enzyme immunoassay, and/or cell cytotoxicity neutralization assay37) and the presence of either ≥3 unformed stools in <24 hours with a duration >24 hours, endoscopic/histologic evidence of pseudomembranous colitis, or ileus.
• Because of the prohibitive cost of fidaxomicin, the reimbursement criteria of fidaxomicin by the Régie de l'assurance maladie du Québec will be applied as inclusion criteria until dedicated fidaxomicin funding is available. This includes: either 1) ≥65 years old or immunosuppression, 2) a second episode of C. difficile within 12 weeks of a prior episode of C. difficile, or 3) multiply recurrent CDI (i.e., ≥2 recurrences). When additional funding is obtained, then only inclusion criteria 1 and 2 will be applied.

Exclusion criteria

• Planned or current treatment of the present episode of CDI with FMT, intravenous immunoglobulins, or other microbiome therapies (i.e., VOWST or REBYOTA).
• Inability to take medications orally or crushed by tube.
• Prior total colectomy.
• Severe intolerance or allergy to oral vancomycin or fidaxomicin.
• Patient is being admitted to a palliative care ward or is anticipated to die within 3 months of enrollment from another illness.
• Fulminant CDI, defined according to the IDSA definition of CDI with the presence of hypotension, shock, ileus, and/or toxic megacolon. This is because vancomycin is generally preferred at this severity.
• Receipt of more than 72 hours of off-study fidaxomicin or vancomycin CDI therapy for the current episode of CDI.
• Pregnancy or planning to become pregnant during the study period because minimal data on fidaxomicin in pregnancy are available.
• Active breastfeeding because minimal data on fidaxomicin in breastfeeding are available.
• Prior enrollment in this trial.
• Inability to consent without a healthcare proxy.
• Lack of health insurance.
• Anticipated transfer to a site not involved in this trial, or to a palliative care ward.
• Patient declared anticipated inability to participate in study follow-up or lack of means for contact in the outpatient setting.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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500 participants in 2 patient groups

Fidaxomicin

Active Comparator group

Description:

Fidaxomicin 200mg PO BID x 10 days

Treatment:

Drug: Fidaxomicin

Vancomycin T-P

Experimental group

Description:

Vancomycin 125mg PO QID x2 weeks, then 125mg PO BID x2 weeks, then 125mg PO daily x2 weeks

Treatment:

Drug: Vancomycin capsule