VanC-IT: A Phase 2 Randomized Trial of Oral Vancomycin in Primary Sclerosing Cholangitis

The VanC-IT trial is a phase 2 clinical study designed to evaluate the efficacy and safety of oral vancomycin in patients with primary sclerosing cholangitis (PSC), a chronic and progressive liver disease for which no approved disease-modifying therapies currently exist. PSC is characterized by inflammation and scarring of the bile ducts, leading to cholestasis (impaired bile flow), liver damage, and eventually liver failure. Liver transplantation remains the only definitive treatment for PSC. Additionally, PSC is often associated with inflammatory bowel disease (IBD), though the disease can occur independently of IBD.

### Study Design:

The VanC-IT trial is a **prospective, randomized, double-blind, placebo-controlled phase 2 study**, meaning participants are randomly assigned to either the treatment group (oral vancomycin) or the placebo group, and neither the participants nor the researchers know which treatment is being administered (double-blind design). This ensures unbiased assessment of the efficacy and safety of oral vancomycin.

The trial is **conducted in Italy** and includes both adult and adolescent patients diagnosed with PSC, regardless of whether they have IBD. Eligible participants undergo a screening process and are stratified based on their baseline liver stiffness before randomization. This stratification ensures that differences in liver stiffness, which is a marker of liver disease severity, are accounted for during analysis.

### Rationale:

The rationale for investigating oral vancomycin in PSC stems from emerging evidence that implicates the **gut–liver axis** and **microbiome alterations** in the pathogenesis of PSC. The gut–liver axis refers to the bidirectional relationship between the gastrointestinal tract and the liver, which is influenced by microbial populations in the gut. Alterations in the microbiome may play a role in driving inflammation and immune dysregulation seen in PSC. Oral vancomycin, an antibiotic, has been hypothesized to modulate the gut microbiome and reduce inflammation, making it a potential therapeutic option for PSC.

### Objectives:

The trial aims to assess the impact of oral vancomycin on disease activity, with a focus on both efficacy and safety. The study is designed to generate high-quality evidence to inform future therapeutic strategies for PSC.

#### Primary Outcome:

The primary outcome of the VanC-IT trial is **changes in biochemical markers of cholestasis**, which reflect treatment response. These markers include measurements such as alkaline phosphatase (ALP), bilirubin levels, and other indicators of bile duct function.

#### Secondary Outcomes:

The secondary outcomes are more comprehensive and include:

• Liver biochemistry (e.g., liver enzyme levels).
• Disease risk scores (such as the Mayo Risk Score for PSC).
• Imaging findings (e.g., changes in liver stiffness or bile duct abnormalities).
• Circulating biomarkers related to inflammation and liver function.
• Quality of life assessments (to evaluate the impact of treatment on patients' overall well-being).
• PSC-related clinical events (e.g., episodes of cholangitis or disease progression).

#### Exploratory Outcomes:

An important exploratory component of the trial involves investigating treatment-related biological mechanisms, with a focus on:

• **Gut microbiota analysis**: Understanding how oral vancomycin affects microbial populations in the gut.
• **Metabolomic profiling**: Identifying changes in metabolic pathways that may be linked to treatment effects.
• **Immunological markers**: Evaluating immune system changes and inflammatory responses related to treatment.

### Significance:

The VanC-IT trial is expected to provide valuable insights into the role of oral vancomycin as a potential therapy for PSC. By rigorously evaluating its efficacy and safety, the trial aims to address the unmet need for disease-modifying treatments in PSC. Additionally, the study’s exploratory analyses may shed light on microbiome-related pathways and mechanisms underlying PSC, which could guide the development of future therapeutic strategies.

### Expected Outcomes:

The findings from the VanC-IT trial are anticipated to:

1. Inform the design of larger, definitive clinical trials in PSC management.

2. Provide evidence on the utility of microbiome-targeted therapies in PSC.

3. Improve understanding of the gut–liver axis and its role in PSC pathogenesis.

In summary, the VanC-IT trial represents a critical step toward developing effective treatments for PSC, a disease with limited therapeutic options. By investigating oral vancomycin, the study aims to address the urgent need for evidence-based therapies while expanding knowledge of PSC-related biological mechanisms.