Primary Sclerosing Cholangitis, Liver and Intrahepatic Bile Duct Disorder, IBD
Conditions
Keywords
liver, oral vancomycin, primary sclerosing cholangitis, Inflammatory bowel disease
Brief summary
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
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.
Interventions
DRUGOral 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.
OTHERPlacebo
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.
Sponsors
Genetic s.p.a.
University of Milano Bicocca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
During the randomization phase, subjects and all personnel directly involved in the conduct of the study will be blinded to the treatment assignment.
Intervention model description
Group A: vancomycin 750 mg daily Group B: vancomycin1500mg daily Group C: placebo
Eligibility
Sex/Gender
ALL
Age
15 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in alkaline phosphatase (ALP) levels | From baseline to 6 months | ALP levels at 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical hematology | From baseline to 6 months | White blood cells (10\^3/uL) |
| Clinical chemistry | From baseline to 6 months | Total proteins (g/dl) |
| Single 12-lead electrocardiograms | From baseline to 6 months | Sinus rhythm |
| Urine analysis | From baseline to 6 months | pH |
| Vital sign measurements | From baseline to 6 months | Body weight (kg) |
| Changes in the PSC score | From baseline to 6 months | 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) |
| Safety and tolerability of OV in each treatment arm | From baseline to 6 months | Adverse events |
| Liver stiffness measurements | From baseline to 6 months | Stiffness (kPa/s) |
| MRCP (Magnetic Resonance Cholangiopancreatography) | From baseline to 6 months | Disease localisation |
| Cytokines changes | From baseline to 6 months | TGF-β levels |
| Changes in the peripheral blood mononuclear cells | From baseline to 6 months | Th1 and Th17 subsets isolation and analyses |
| Patients quality of life | From baseline to 6 months | Visual analogue scale (VAS) score for itch |
| Changes in the IBD score | From baseline to 6 months | Clinical Mayo Score (Partial Mayo Score) -(0-1=Remission; 2-4 = Mild activity; 5-7 = Moderate activity; 7-9 = Severe activity) |
Countries
Italy
Contacts
Primary ContactMarco Carbone, MD
Backup ContactPietro Invernizzi, MD
Outcome results
None listed