Double blind, multicentric, randomized, placebo-controlled trial, evaluating the efficacy of 24-month of bezafibrate in primary sclerosing cholangitis with persistent cholestasis despite ursodeoxycholic acid therapy (BEZASCLER

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

6 Apr 2021 → ongoing

Decision date (initial)

2024-09-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-511658-28-01

EudraCT number

2019-001015-23

ClinicalTrials.gov

NCT04309773

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

To assess the efficacy of 24-month treatment with bezafibrate (400 mg SR/d) versus placebo in addition to standard UDCA therapy in primary sclerosing cholangitis

Secondary objectives 9

1. 1- To compare between groups components of the primary composite outcome at M24
2. To compare between groups Adverse effects including IBD activity hepatic, muscular, and kidney function
3. To compare between groups Quality of life and scores for pruritus and fatigue at M12 and M24
4. To compare between groups changes in liver tests between M0 and M24
5. To compare between groups occurrence of clinical events and transplant-free survival
6. Changes in serum markers of fibrosis (ELF score and Pro-C3) and cholangiographic abnormalities between M0 and M24
7. - Course of biomarkers (including microbiota) and correlation with observed effects between M0 and M24
8. - Need for endoscopic procedures between M0 and M24
9. - Changes in liver tests and creatinin 3 to 6 months after experimental treatment discontinuation

Conditions and MedDRA coding

primary sclerosing cholangitis

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. • Males or females ≥ 18 and ≤ 75 years
2. • Large duct PSC verified by retrograde, operative, percutaneous or magnetic resonance cholangiography (MRC) demonstrating intrahepatic and /or extrahepatic biliary duct changes consistent with PSC
3. • Colonoscopy (already done or scheduled before randomization) within the last 5 years (or within 6 months if IBD is associated to PSC) with neither cancer nor all-grade dysplasia or endoscopy of the ileal reservoir (already done or scheduled before randomization) within the last 2 years in patients with ileo-anal anastomosis.
4. • ALP ≥ 1.5 ULN
5. • Traitement par l'AUDC (13-23 mg/kg/j) depuis ≥ 6 mois avant l'inclusion (Arrondi à l’unité le plus proche, par exemple 12.5 mg/kg/j arrondi à 13 mg/kg/j)
6. • Using contraceptive in women of childbearing potential. Women of childbearing potential, i.e. fertile, following menarche and until becoming post-menopaused unless permanently sterile, who are sexually active have to apply a highly effective method of birth control with a low failure rate (i.e. less than 1% per year) when used constantly and correctly.
7. • Affiliation to a social security system (AME excepted)
8. • Signed informed consent

Exclusion criteria 28

1. • Child-Pugh score B or C
2. • Current or recent history (within 2 years) of clinically detectable Ascites or digestive hemorrhage
3. • Total bilirubin in the last 3 months > 50 μmole/L (3 mg/dl)
4. • Gilbert syndrome defined as unconjugated bilirubinemia > LSN in the last 3 months (according to the laboratory reference value)
5. • Albumin in the last 3 months < LLN (according to the laboratory reference value)
6. • Prothrombin index in the last 3 months < 70%
7. • Platelets count in the last 3 months < 100000/mm3
8. • ALT or AST > 5 ULN in the last 3 months
9. • Prior liver transplantation
10. • Treatment with a fibrate within the last 3 months inclusion
11. • Current active IBD defined as either current use of systemic corticosteroid therapy > 10 mg/day or budesonide > 3 mg /day or immunosuppressive drugs (cyclosporine, tacrolimus, mycophenolate mofetil, mTor inhibitors, JAK inhibitors) or a partial Mayo score > 2 in patients with ulcerative colitis (UC), unclassed colitis or a Crohn’s Disease Activity Index (CDAI) > 150 in patients with Crohn’s disease (CD)
12. • Dosage change of treatment for associated IBD ≤3 months prior to inclusion
13. • Current or history of colonic cancer or all-grade dysplasia described at the last colonoscopy (Patients with a history of colon cancer and treated by total colectomy without recurrence for at least 5 years are eligible)
14. • Any other cause of liver damage ((positive test for HBV, HCV, or HIV, excessive alcohol consumption, hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, celiac disease
15. • Current or recent history (within 2 years) of Autoimmune hepatitis defined by the presence of interface hepatitis documented on liver biopsy and at least 1 of the 2 following criteria: 1) AST or ALT > 5 ULN, 2) Positive anti smooth muscle auto antibodies or serum IgG > 1.5 ULN
16. • Secondary causes of sclerosing cholangitis including IgG4-associated cholangitis (elevated serum IgG4 > 4 ULN)
17. • History of acute cholangitis in the last 3 months prior to inclusion or current acute cholangitis or suspected cholangiocarcinoma.
18. • Endoscopic treatment for bile duct stenosis ≤ 3 months prior to inclusion or planned within 3 months post randomization date
19. • History of or established or suspected hepatobiliary carcinoma
20. • Any severe comorbidity that may reduce life expectancy
21. • History of malignancy diagnosed or treated within 2 years (recent localized treatment of squamous or non-invasive basal skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to Screening)
22. • Known hypersensitivity to bezafibrate, any of the components of Befizal© or other fibrates
23. • Known photosensitivity or photoallergy reactions to fibrate
24. • Patient with congenital galactosemia, glucose malabsorption, or lactase deficiency because of presence of lactose in 400 mg SR tablets of bezafibrate and in placebo tablets
25. • Pregnancy (or desire for)
26. • Renal insufficiency (clearance < 60 ml/min or serum creatinine level > 130 μmole/L)
27. • Breastfeeding
28. • Participation in any other interventional study or in the exclusion period any other interventional study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of patients with serum Alkaline Phosphatase < 1.5 ULN and a reduction of at least 15% from baseline at M24 and normal serum bilirubin and no increase of liver stiffness at M24 compared to baseline (delta M24–M0 ≤ 0).

Secondary endpoints 6

1. To compare between groups - Components of the primary composite outcome analyzed separately: Proportion of patients with: - serum Alkaline Phosphatase < 1.5 ULN at M24 and at least 15% of decrease from baseline at M24; - complete normalization of s-ALP at M24 (s-ALP ≤ 1.0 ULN at M24); - normal serum bilirubin; - no increase in liver stiffness at M24
2. To compare between groups - Safety endpoint: Percentage of patients with clinical (including increased IBD activity) or biological
3. To compare between groups: - Quality of life (QMCF questionnaire – Questionnaire de la maladie chronique du foie) and scores for pruritus (measured by VAS and 5D pruritus scale) and fatigue (measured by adapted PBC-40 questionnaire (M0, M12 and M24))
4. To compare between groups: Changes in Patient-Reported Outcomes (PRO) specific for PSC (45).
5. To compare between groups: - Changes in biochemical liver tests other than ALP, including total and conjugated bilirubin, GGT, AST, ALT, albumin, and INR,
6. To compare between group survival rate without liver transplantation or hepatic events (ascites, variceal bleeding, encephalopathy, acute cholangitis, cholangiocarcinoma, hepatocellular carcinoma or serum total bilirubin > 100 μmol/L for at least 3 months). PSC Prognostic scores including the MELD score, the Revised PSC Mayo Risk Score, the Hannover Score and the Amsterdam-Oxford prognostic model (M0, M12, M24)

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Olivier CHAZOUILLERES

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Olivier CHAZOUILLERES

Locations

1 EU/EEA country · 35 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 8 files

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

Application history

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