Vancomycin in Primary Sclerosing Cholangitis in Italy (VanC-IT)

A Prospective, Randomized, Placebo-controlled Clinical Trial of Oral Vancomycin in Adults and Young Adults (15-17 Years Old) Affected by Primary Sclerosing Cholangitis With or Without Inflammatory Bowel Disease

Primary sclerosing cholangitis (PSC) is chronic fibroinflammatory disease of the liver. There is still no medical therapy proven to halt the progression of PSC or prevent its serious complications.

This is a Phase 2 randomized, double bind, placebo-controlled, monocentric study evaluating the safety and efficacy of two doses of oral vancomycin (i.e. 750 mg and 1500 mg/day) in subject between 15 - 70 years old with PSC.

Study Overview

• Status: Recruiting
• Conditions: Primary Sclerosing Cholangitis; IBD; Liver and Intrahepatic Bile Duct Disorder
• Intervention / Treatment: Drug: Oral Vancomycin; Other: Placebo

Detailed Description

Primary sclerosing cholangitis (PSC) is chronic fibroinflammatory disease of the liver characterized by chronic inflammation and sclerosis of the intrahepatic and/or extrahepatic bile ducts, and a risk for progression to liver failure and development of colorectal and hepatobiliary cancer. Both children and adults are affected. Patients with PSC have a diminished life expectancy with a median survival of 17 years after diagnosis. Despite the high mortality associated with PSC and the efforts to optimize its management, there is no medical therapy proven to halt the progression of PSC or prevent its serious complications. There is a strong yet poorly understood relationship between PSC and inflammatory bowel disease (IBD); nearly 70%-80% of PSC patients have IBD, mainly ulcerative colitis (UC). Increasing evidence is pointing out the role of gut microbiota in the pathogenesis of PSC. The 'leaky gut' theory implies that either bacteria or their toxic metabolites translocate from the inflamed intestinal mucosa into the portal circulation and into the liver causing liver and biliary injury. The gut microbiota of PSC patients, compared to IBD patients and healthy controls, showed decreased microbial diversity, and over-represented intestinal pathobionts (i.e., organisms which, under normal circumstances, lives as a non-harming symbiont). Several antibiotics, including vancomycin and metronidazole, have been investigated in PSC. The use of oral vancomycin (OV), a glycopeptide antibiotic has been reported to be associated with improvement in clinical symptoms and laboratory abnormalities in patients with PSC; however, prospective studies in adult and young adult patients in Europe are lacking.

Our scientific community therefore seeks to examine the safety and efficacy of OV in patients with PSC in a randomized placebo-controlled clinical trial.

This is a Phase 2 randomized, double bind, placebo-controlled, monocentric study evaluating the safety and efficacy of two doses of oral vancomycin (i.e. 750 mg and 1500 mg/day) in subject between 15 - 70 years old with PSC with or without IBD. The study will consist of 10-week screening period (including a run-in phase), 24 weeks of treatment, and follow-up visits at 4 and 12 weeks after completion of treatment to evaluate what happens after treatment stop. Subjects will be randomized to placebo or treatment and stratifying by baseline presence of fibrosis by fibroscan value at baseline (< or ≥14.4 kPa corresponding to F4 fibrosis), as this parameter could affect the likelihood of reaching the primary composite outcome measure.

The knowledge gained from our proposed clinical trial will help us determine if OV should be considered as a treatment option in patients with PSC. Furthermore, the use of state-of-the art technology applied in this study will shed light on the relationship between the gut microbiome, bile acids, immune-mediators, including cytokines, and PSC.

• Study Type: Interventional
• Enrollment (Estimated): 84
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pietro Invernizzi, MD; Phone Number: 039 233 2187; Email: pietro.invernizzi@unimib.it
• Study Contact Backup: Name: Marco Carbone, MD; Phone Number: 0392334515; Email: marco.carbone@unimib.it

Study Locations

• Italy
  • Monza E Brianza
    • Monza, Monza E Brianza, Italy, 20900
      • Recruiting
      • Fondazione IRCCS San Gerardo dei Tintori
      • Contact: Marco Carbone, MD; Phone Number: 0392334515; Email: marco.carbone@unimib.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Willing and able to give informed consent prior to any study specific procedure being performed;
2. Male and non-pregnant, non-lactating female subjects, including women of child bearing potential (WOCBP), between 15-70 years of age at the time of informed consent;
3. Diagnosis of large-duct PSC based on cholangiogram (at MRCP, ERCP, PTC) according to the most recent published guidelines (EASL);
4. Baseline ALP ≥1.5 times upper limit normal at screening;
5. Absence of biliary obstruction and/or malignancy within 6-12 months of entry into the study;
6. If a patient is on ursodeoxycholic acid (UDCA) or 5-aminosalicylic acid he or she is expected to remain on the same daily dose during the study period;
7. Patients who received antibiotics or probiotics may participate if they had a washout period of at least 3-month prior to study entry;
8. If a patient has been on obeticholic acid or other experimental therapies (e.g. cilofexor and norUDCA) for PSC, they must complete a 3-month washout period before study entry;
9. PSC with or without IBD. IBD diagnosis should be documented and with a minimum disease duration of 6 months, as determined by endoscopic and histopathology assessment. IBD should be in clinical remission or mildly active according to CDAI and partial Mayo score for CD and UC, respectively (i.e. patients with CDAI score < 220 and pMayo score <5). Patients without documented IBD need a colonoscopy with segmental biopsies within 12 months prior to baseline visit;
10. Female subjects of childbearing potential must test negative for pregnancy at screening, baseline and follow-up visits and if engage in sexual intercourse must agree to use specific methods of contraception.
11. Male subjects with female partners of childbearing potential must use condoms during treatment and until the end of relevant systemic exposure.

Exclusion Criteria:

1. Receiving an antibiotic or probiotic within 3 months prior to the study;
2. Expected to receive antibiotics within the weeks leading up to enrollment (such as patients with recurrent cholangitis, ongoing infectious illnesses, etc.);
3. Allergy to vancomycin or teicoplanin;
4. Biliary intervention within 3 months prior to study enrollment or planned;
5. Alcohol abuse (defined as greater than 14 standard drinks units per week in men; greater than 7 standard drinks units per week);
6. Pregnancy and lactation;
7. Advanced renal disease (GFR< 70);
8. Active hepatitis B and/or C infection;
9. Other chronic or cholestatic liver diseases such as PBC, autoimmune hepatitis, nonalcoholic steatohepatitis, alcoholic liver disease, Wilson's disease, hemochromatosis, α-1 antitrypsin deficiency, IgG4-related sclerosing cholangitis, and liver cancer;
10. History of CCA;
11. Advanced liver disease (history of variceal bleeding, ascites, hepatic encephalopathy, and/or bilirubine >4 mg/dL);
12. On active transplantation list;
13. IBD with uncontrolled moderate to severe activity;
14. Active treatment or within the previous four weeks (washout period) with any immunosuppressive medication for controlling IBD (i.e. azathioprine, 6-mercaptopurine, tacrolimus, methotrexate, infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, ozanimod). Treatment with corticosteroids (including budesonide, budesonide MMX and beclomethasone) in the previous four weeks
15. Active treatment with rifampicin or within the previous three months (washout period);
16. Dose change within last 3 months prior to baseline of concomitant treatment with vitamin D or fibrates;
17. Treatment with any experimental drug within the previous three months;
18. Any known relevant infectious disease (e.g. active tuberculosis, AIDS defining disease);
19. History or active hearing problems;
20. Any active malignant disease;
21. Well found doubt about patient's cooperation, e.g. addiction to alcohol or drugs;
22. Imprisoned person, person admitted to nursing homes, persons under legal guardianship, and persons not able to express their consent.

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
Experimental: Oral Vancomycin 750; 28 subjects with PSC will be randomized to this arm. They will take 2 tablet (1 of vancomycin 250 mg and 1 of placebo), three times a day administered orally (total dose 750 mg/daily).	Drug: Oral Vancomycin; The investigator will identify potential participants and confirm the diagnosis of PSC. Subjects will be screened within 10 weeks before randomization to determine the eligibility. Study participants will be consecutively randomized to oral vancomycin or placebo and investigational drug and placebo dispensed.; Other Names: OV
Experimental: Oral Vancomycin 1500; 28 subjects with PSC will be randomized to this arm.They will take 2 tablet of 250 mg of vancomycin three times a day administered orally (total dose 1500mg/daily)	Drug: Oral Vancomycin; The investigator will identify potential participants and confirm the diagnosis of PSC. Subjects will be screened within 10 weeks before randomization to determine the eligibility. Study participants will be consecutively randomized to oral vancomycin or placebo and investigational drug and placebo dispensed.; Other Names: OV
Placebo Comparator: Placebo; 28 subjects with PSC will be randomized to this arm. They will take 2 tablet (placebo-to-match oral vancomycin) administered orally three times a day.	Other: Placebo; The investigator will identify potential participants and confirm the diagnosis of PSC. Subjects will be screened within 10 weeks before randomization to determine the eligibility. Study participants will be consecutively randomized to oral vancomycin or placebo and investigational drug and placebo dispensed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in alkaline phosphatase (ALP) levels	ALP levels at 6 months	From baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of OV in each treatment arm	Adverse events	From baseline to 6 months
Clinical hematology	White blood cells (10^3/uL)	From baseline to 6 months
Clinical hematology	Hemoglobin (g/dl)	From baseline to 6 months
Clinical hematology	Hematocrit (%)	From baseline to 6 months
Clinical hematology	MCV (Mean Corpuscular Volume) (fL)	From baseline to 6 months
Clinical hematology	Platelets (10^3/uL)	From baseline to 6 months
Clinical hematology	Absolute neutrophils (10^3/uL)	From baseline to 6 months
Clinical hematology	Absolute lymphocytes (10^3/uL)	From baseline to 6 months
Clinical hematology	PT (Prothrombin Time, Ratio)	From baseline to 6 months
Clinical hematology	INR	From baseline to 6 months
Clinical chemistry	Total proteins (g/dl)	From baseline to 6 months
Clinical chemistry	Albumin (g/dl)	From baseline to 6 months
Clinical chemistry	Gamma (g/dl)	From baseline to 6 months
Clinical chemistry	Sodium (mmol/l)	From baseline to 6 months
Clinical chemistry	Creatinine (mg/dl)	From baseline to 6 months
Clinical chemistry	Potassium (mmol/l)	From baseline to 6 months
Clinical chemistry	Urea (mg/dl)	From baseline to 6 months
Clinical chemistry	Glucose (mg/dl)	From baseline to 6 months
Clinical chemistry	Total bilirubin (mg/dl)	From baseline to 6 months
Clinical chemistry	Direct bilirubin (mg/dl)	From baseline to 6 months
Clinical chemistry	GGT (U/l)	From baseline to 6 months
Clinical chemistry	AST (U/l)	From baseline to 6 months
Clinical chemistry	ALT (U/l)	From baseline to 6 months
Clinical chemistry	Triglycerides (mg/dl)	From baseline to 6 months
Clinical chemistry	Cholesterol (Total) (mg/dl)	From baseline to 6 months
Clinical chemistry	High Density Lipoprotein (HDL Cholesterol) (mg/dl)	From baseline to 6 months
Clinical chemistry	PCR (C Reactive Protein) (mg/dl)	From baseline to 6 months
Clinical chemistry	IgG (mg/dl)	From baseline to 6 months
Clinical chemistry	IgA (mg/dl)	From baseline to 6 months
Clinical chemistry	IgM (mg/dl)	From baseline to 6 months
Clinical chemistry	Ferritin (ng/ml)	From baseline to 6 months
Single 12-lead electrocardiograms	Sinus rhythm	From baseline to 6 months
Single 12-lead electrocardiograms	QTc (msec)	From baseline to 6 months
Urine analysis	pH	From baseline to 6 months
Urine analysis	Specific gravity	From baseline to 6 months
Urine analysis	Hemoglobin	From baseline to 6 months
Urine analysis	ACR (mg/g)	From baseline to 6 months
Urine analysis	PCR (mg/g)	From baseline to 6 months
Vital sign measurements	Body weight (kg)	From baseline to 6 months
Vital sign measurements	Systolic blood pressure (mmHg)	From baseline to 6 months
Vital sign measurements	Diastolic blood pressure (mmHg)	From baseline to 6 months
Vital sign measurements	Heart Rate (bpm)	From baseline to 6 months
Vital sign measurements	Temperature (°C)	From baseline to 6 months
Changes in the PSC score	Revised Mayo Risk Score (Calculation formula = 0.03 (age [y]) + 0.54 loge (bilirubin [mg/dL]) + 0.54 loge (aspartate aminotransferase [U/L]) + 1.24 (variceal bleeding [0/1]) - 0.84 (albumin [g/dL]) (Higher scores indicate greater disease severity)	From baseline to 6 months
Changes in the IBD score	Clinical Mayo Score (Partial Mayo Score) -(0-1=Remission; 2-4 = Mild activity; 5-7 = Moderate activity; 7-9 = Severe activity)	From baseline to 6 months
Liver stiffness measurements	Stiffness (kPa/s)	From baseline to 6 months
Liver stiffness measurements	Stiffness IQR/median (%)	From baseline to 6 months
Liver stiffness measurements	CAP (dB/m)	From baseline to 6 months
Liver stiffness measurements	CAP IQR/median (%)	From baseline to 6 months
MRCP (Magnetic Resonance Cholangiopancreatography)	Disease localisation	From baseline to 6 months
MRCP (Magnetic Resonance Cholangiopancreatography)	Presence of dominant stenosis	From baseline to 6 months
MRCP (Magnetic Resonance Cholangiopancreatography)	Radiological signs of cirrhosis	From baseline to 6 months
Cytokines changes	TGF-β levels	From baseline to 6 months
Cytokines changes	IL-4 levels	From baseline to 6 months
Cytokines changes	IL-13 levels	From baseline to 6 months
Cytokines changes	IL-10 levels	From baseline to 6 months
Changes in the peripheral blood mononuclear cells	Th1 and Th17 subsets isolation and analyses	From baseline to 6 months
Patients quality of life	Visual analogue scale (VAS) score for itch	From baseline to 6 months
Patients quality of life	Chronic Liver Disease Questionnaire (CLDQ)	From baseline to 6 months
Patients quality of life	EQ-5D-5L questionnaire	From baseline to 6 months
Patients quality of life	PSC patient reported outcome (PSC-PRO) questionnaire	From baseline to 6 months
Patients quality of life	Inflammatory Bowel Disease Questionnaire (IBDQ)	From baseline to 6 months

Collaborators and Investigators

• Sponsor: University of Milano Bicocca
• Collaborators: Genetic s.p.a.

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: March 10, 2023
• First Submitted That Met QC Criteria: May 16, 2023
• First Posted (Actual): May 25, 2023

Study Record Updates

• Last Update Posted (Actual): July 25, 2025
• Last Update Submitted That Met QC Criteria: July 24, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: liver; Inflammatory bowel disease; primary sclerosing cholangitis; oral vancomycin
• Additional Relevant MeSH Terms: Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Biliary Tract Diseases; Gastroenteritis; Liver Diseases; Cholangitis; Cholangitis, Sclerosing; Inflammatory Bowel Diseases; Bile Duct Diseases; Anti-Bacterial Agents; Anti-Infective Agents; Vancomycin
• Other Study ID Numbers: VanC-IT

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: No
• Studies a U.S. FDA-regulated device product: No