Clinical study in adults and young patients with Primary Sclerosing Cholangitis treated with oral vancomycin or placebo

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Of Milano Bicocca

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

15 Jun 2023 → ongoing

Decision date (initial)

2023-12-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

GENETIC S.p.A.

External identifiers

EU CT number

2023-507425-42-00

EudraCT number

2022-000875-37

ClinicalTrials.gov

NCT05876182

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To compare the effect of OV at different doses versus placebo on alkaline phosphatase (ALP) at 6 months

Secondary objectives 2

1. - To determine the safety and tolerability of OV in each treatment arm;
2. - To evaluate the effect of OV at different doses versus placebo at 6 months on the following: • liver fibrosis assessed by liver stiffness measurements (LSM) using transient elastography (TE) • magnetic resonance cholangiopancreatography (MRCP) traditional semiquantitative scoring (Amsterdam criteria/Anali criteria) and continuous scoring using MRCP+ & Liver multiscan technology (Perspectum Diagnostics Ltd) • non-invasive biomarkers of liver fibrosis (ELF, PRO-C3, PRO-C5; C3M, C4M and BGM), cell apoptosis and necrosis (CK18 M30 and M65), cytokines (TGF-ß, IL-4, IL-13, IL-10, etc.) peripheral blood mononuclear cells (Th1 and Th17 subsets), and biomarkers of farnesoid-X-receptor (FXR) activity (FGF-19, C4 and bile acid)• clinical, endoscopic and histologic activity of IBD • quality of life

Conditions and MedDRA coding

Primary Sclerosing Cholangitis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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, 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 1

1. 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 (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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ALP levels at 6 months

Secondary endpoints 14

1. reduction of ALP levels =40% (for those of 15-17-year-old the liver isoenzyme will be evaluated)
2. safety and tolerability: adverse events, clinical hematology, clinical chemistry, urinalysis, single 12-lead electrocardiograms (ECGs), vital sign measurements including body weight, systolic and diastolic blood pressure (BP), body temperature and pulse rate. Rectal swab to exclude infection or colonisation with vancomycinresistant enterococci (VRE)
3. reduction of serum gammaglutamyltransferase (GGT) levels
4. reduction of serum aspartate-aminotransferase (AST) and Alanine-aminotransferase (ALT) levels
5. normalization of serum bilirubin levels
6. change in Amsterdam-Oxford prognostic score
7. change in the Revised PSC Mayo Risk Score
8. lack of progression in LSM at FibroScan (change in liver stiffness <= 1.3 kPa)
9. lack of progression in bile duct strictures and dilatation (evaluated at MCRP using traditional semiquantitative scoring such as Anali criteria)
10. change in non-invasive biomarkers of liver fibrosis (ELF, PRO-C3, PRO-C5; C3M, C4M and BGM), cell apoptosis and necrosis (CK18 M30 and M65), cytokines (TGF-ß, IL-4, IL- 13, IL-10, etc.) peripheral blood mononuclear cells (Th1 and Th17 subsets), and biomarkers of FXR activity (FGF-19, C4 and bile acid)
11. changes in IBD activity indexes: Crohn's Disease Activity Index [CDAI] score and partial Mayo score [pMCS], for Crohn’s disease [CD] and UC respectively; changes in Creactive protein (CRP) and fecal calprotectin levels; changes in Simple Endoscopic Score for Crohn’s Disease [SES-CD] and endoscopic Mayo score, for CD and UC respectively; changes in Nancy Histological Index for UC and Global Histologic Disease Activity Score [GHAS] for CD
12. proportion of patients who are in clinical remission (defined as CDAI<150 for CD or partial Mayo Score <2 for UC) at baseline, week 4, 12 and 24. and week 12 of follow up; proportion of patients achieving endoscopic remission (defined as SES-CD = 2 for CD or endoscopic Mayo score <1 for UC) at baseline and week 24; proportion of patients achieving histologic healing (as defined as GHAS =4 for CD or Nancy Histological Index <1 for UC) at baseline and week 24
13. changes in ultrasound activity indices (lesion length, bowel wall thickness, color Doppler signals, bowel wall stratification, inflammatory mesenteric fat, and intestinal complications) at week 24
14. changes in health-related quality of life: visual analogue scale (VAS) score for itch, Chronic Liver Disease Questionnaire (CLDQ), EQ-5D-5L questionnaire, PSC patient reported outcome (PSC-PRO) questionnaire, Inflammatory Bowel Disease Questionnaire (IBDQ)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Of Milano Bicocca

Sponsor organisation

University Of Milano Bicocca

Address

Piazza Dell'ateneo Nuovo 1

City

Milan

Postcode

20126

Country

Italy

Scientific contact point

Organisation

University Of Milano Bicocca

Contact name

Scientific coordinator

Public contact point

Organisation

University Of Milano Bicocca

Contact name

Scientific coordinator

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications