A Randomized, Placebo-Controlled Trial of Oral Vancomycin in Adults and Adolescents with Primary Sclerosing Cholangitis with or without Inflammatory Bowel Disease
- Trial ID
- 2023-507425-42-00
- Protocol
- VanC-IT
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to compare the effect of **oral vancomycin (OV)** at different doses versus placebo on alkaline phosphatase (ALP) levels at 6 months in patients with **Primary Sclerosing Cholangitis**. ALP is a clinically relevant biomarker for liver function, and its reduction could indicate a therapeutic benefit in managing this chronic liver disease.
Secondary objectives include: - To determine the safety and tolerability of OV in each treatment arm. - To evaluate the effect of OV at different doses versus placebo at 6 months on various parameters, including liver fibrosis assessed by liver stiffness measurements using transient elastography, magnetic resonance cholangiopancreatography (MRCP) scoring, non-invasive biomarkers of liver fibrosis, cell apoptosis and necrosis, cytokines, peripheral blood mononuclear cells, biomarkers of farnesoid-X-receptor activity, clinical, endoscopic and histologic activity of inflammatory bowel disease (IBD), and quality of life.
Participants
The clinical trial focuses on individuals diagnosed with **Primary Sclerosing Cholangitis** (PSC), specifically targeting a population that includes both male and female subjects aged between 15 and 70 years. Participants are required to have a diagnosis of large-duct PSC based on cholangiogram, with a baseline alkaline phosphatase (ALP) level of at least 1.5 times the upper limit of normal. The study population includes individuals with or without inflammatory bowel disease (IBD), provided that IBD is in clinical remission or mildly active. Participants must not have biliary obstruction or malignancy within 6-12 months prior to the study. Those on medications such as ursodeoxycholic acid or 5-aminosalicylic acid are expected to maintain their dosage throughout the study. Additionally, individuals previously on obeticholic acid or other experimental therapies must undergo a 3-month washout period before entering the trial. The trial includes a vulnerable population, and female participants of childbearing potential are required to test negative for pregnancy and adhere to specific contraceptive methods. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy and safety of oral **vancomycin** in adults and young adults aged 15-17 years with **Primary Sclerosing Cholangitis** (PSC), with or without Inflammatory Bowel Disease (IBD). The trial aims to compare the effect of vancomycin at different doses versus placebo on alkaline phosphatase (ALP) levels over a period of six months. The study is expected to conclude by June 15, 2026, with recruitment having commenced on June 15, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis of large-duct PSC, and baseline ALP levels. Following successful screening, participants will be randomized to receive either vancomycin or placebo. The trial includes follow-up visits at regular intervals to monitor safety and efficacy endpoints, including ALP levels, adverse events, and various clinical and laboratory assessments. The end-of-study visit will occur at the conclusion of the 24-week treatment period, where final assessments will be conducted.
The expected duration of participant involvement is approximately 24 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. Participants are required to adhere to specific inclusion criteria, such as maintaining stable doses of certain medications and completing washout periods for others. The primary endpoint is the change in ALP levels at six months, with secondary endpoints encompassing a range of biochemical, clinical, and quality of life measures. The trial is conducted in accordance with ethical guidelines, ensuring informed consent and the safety of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of **vancomycin**, a chemical-origin antibiotic, as the experimental medication. Vancomycin is provided in a pharmaceutical form identified as PHF00230MIG, and is administered orally. The maximum daily dose is 1500 mg, with the same amount being the maximum total dose allowed per day. The treatment period is capped at 24 weeks. The primary objective of the trial is to evaluate the effect of oral vancomycin at different doses on alkaline phosphatase levels in patients with Primary Sclerosing Cholangitis, with or without Inflammatory Bowel Disease.
The study also includes a placebo group, where participants receive placebo capsules. These capsules are composed of Polyethylene glycol 6000, which serves as the excipient. The active ingredient is substituted by the same excipient to achieve the intended filling weight. The placebo is presented in white/white 00 hard gelatin capsules, also administered orally. The placebo serves as a comparator to assess the efficacy of vancomycin in the trial. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the effect of oral vancomycin on **alkaline phosphatase (ALP)** levels at 6 months, which serves as the primary endpoint. Secondary endpoints include a reduction of ALP levels by 40% for participants aged 15-17, where the liver isoenzyme will be specifically evaluated. Additional secondary endpoints encompass safety and tolerability assessments, including adverse events, clinical hematology, clinical chemistry, urinalysis, single 12-lead electrocardiograms (ECGs), and vital sign measurements such as body weight, blood pressure, body temperature, and pulse rate. A rectal swab will be conducted to exclude infection or colonization with vancomycin-resistant enterococci (VRE).
Further secondary endpoints involve the reduction of serum **gammaglutamyltransferase (GGT)**, **aspartate-aminotransferase (AST)**, and **alanine-aminotransferase (ALT)** levels, normalization of serum bilirubin levels, and changes in prognostic scores such as the Amsterdam-Oxford prognostic score and the Revised PSC Mayo Risk Score. The trial will also assess the lack of progression in liver stiffness measured by FibroScan and bile duct strictures and dilatation evaluated at MRCP. Changes in non-invasive biomarkers of liver fibrosis, cell apoptosis, necrosis, cytokines, peripheral blood mononuclear cells, and biomarkers of FXR activity will be measured.
Additionally, changes in inflammatory bowel disease (IBD) activity indexes, including the Crohn's Disease Activity Index (CDAI) score, partial Mayo score, C-reactive protein (CRP), fecal calprotectin levels, and endoscopic scores, will be monitored. The proportion of patients achieving clinical remission, endoscopic remission, and histologic healing at specified timepoints will be recorded. Ultrasound activity indices and changes in health-related quality of life, assessed through various questionnaires, will also be evaluated. These efficacy parameters will be collected and analyzed at baseline, week 4, week 12, week 24, and during follow-up visits.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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, Endoscopic retrograde cholangiopancreatography [ERCP], percutaneous transhepatic cholangiography [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.
Exclusion Criteria
- 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 (glomerular filtration rate [GFR ]< 70); 8. Active hepatitis B and/or C infection; 9. Other chronic or cholestatic liver diseases such as primary biliary cholangitis (PBC), autoimmune hepatitis, nonalcoholic steatohepatitis, alcoholic liver disease, Wilson’s disease, hemochromatosis, a-1 antitrypsin deficiency, IgG4-related sclerosing cholangitis, and liver cancer; 10. History of cholangiocarcinoma [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. Dose change within the last 3 months of any immunosuppressive medication for controlling IBD (i.e. azathioprine, 6-mercaptopurine, tacrolimus, methotrexate, infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, ozanimod) or expected to change or start immunosuppressive medication withing the study period. Treatment with corticosteroids (including budesonide, budesonide MMX and beclomethasone) in the previous four weeks; 15. Treatment with rifampicin; 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. Any active malignant disease; 20. Well found doubt about patient’s cooperation, e.g. addiction to alcohol or drugs; 21. Imprisoned person, person admitted to nursing homes, persons under legal guardianship, and persons not able to express their consent.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 15 Jun 2023 | 84 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
VANCOMYCIN | Test | PHF00230MIG | ORAL USE | 1500 | 24 | SCP32734155 |
Placebo capsules contain the only excipient present in the formulation, Polyethylene glycol 6000; the active ingredient is substituted by the same excipient to obtain the intended filling weight. The pharmaceutical form is white/white 00 hard gelatin capsules for oral administration. | Placebo | N/A | — | — | — | N/A |