Vancomycin in Primary Sclerosing Cholangitis in Italy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Primary Sclerosing Cholangitis, Liver and Intrahepatic Bile Duct Disorder, IBD

Intervention / Treatment
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* Drug: Oral Vancomycin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give informed consent prior to any study specific procedure being performed; 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; Diagnosis of large-duct PSC based on cholangiogram (at MRCP, ERCP, PTC) according to the most recent published guidelines (EASL); Baseline ALP ≥1.5 times upper limit normal at screening; Absence of biliary obstruction and/or malignancy within 6-12 months of entry into the study; 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; Patients who received antibiotics or probiotics may participate if they had a washout period of at least 3-month prior to study entry; 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; 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; 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. Male subjects with female partners of childbearing potential must use condoms during treatment and until the end of relevant systemic exposure. Exclusion Criteria: Receiving an antibiotic or probiotic within 3 months prior to the study; Expected to receive antibiotics within the weeks leading up to enrollment (such as patients with recurrent cholangitis, ongoing infectious illnesses, etc.); Allergy to vancomycin or teicoplanin; Biliary intervention within 3 months prior to study enrollment or planned; Alcohol abuse (defined as greater than 14 standard drinks units per week in men; greater than 7 standard drinks units per week); Pregnancy and lactation; Advanced renal disease (GFR< 70); Active hepatitis B and/or C infection; 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; History of CCA; Advanced liver disease (history of variceal bleeding, ascites, hepatic encephalopathy, and/or bilirubine >4 mg/dL); On active transplantation list; IBD with uncontrolled moderate to severe activity; 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 Active treatment with rifampicin or within the previous three months (washout period); Dose change within last 3 months prior to baseline of concomitant treatment with vitamin D or fibrates; Treatment with any experimental drug within the previous three months; Any known relevant infectious disease (e.g. active tuberculosis, AIDS defining disease); History or active hearing problems; Any active malignant disease; Well found doubt about patient's cooperation, e.g. addiction to alcohol or drugs; Imprisoned person, person admitted to nursing homes, persons under legal guardianship, and persons not able to express their consent.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 70 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
Interventional Model Description: Group A: vancomycin 750 mg daily Group B: vancomycin1500mg daily Group C: placebo
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Vancomycin 750<br>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<br>* 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.<br>* Other names: OV;|
| Experimental: Oral Vancomycin 1500<br>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<br>* 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.<br>* Other names: OV;|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver, oral vancomycin, primary sclerosing cholangitis, Inflammatory bowel disease