Efficacy of IMP reducing liver fibrosis in patients with advanced fibrosis due to alcohol: a randomized, double-blind, placebo-controlled clinical trial.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacio De Recerca Clinic Barcelona-Institut D’Investigacions Biomediques August Pi I Sunyer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

11 Dec 2024 → ongoing

Decision date (initial)

2024-12-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-519968-41-00

EudraCT number

2020-006023-33

ClinicalTrials.gov

NCT04971577

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Proportion of patients with a significant reduction in the degree of liver fibrosis after treatment with simvastatin compared to placebo, analyzed through the histological evaluation of fibrosis using the Ishak scale, defined as a reduction in the fibrosis value of at least one point on the scale.

Secondary objectives 6

1. Analyze the effect of simvastatin on liver fibrosis applied by non invasive methods: a. Transient liver elastography. b. Magnetic resonance elastography (MRA). c. Serum markers and liver fibrosis score validated for ALD and widely used in the general population: FIB-4 (Fibrosis Index for Liver Fibrosis) and ELF (Enhanced Liver Fibrosis), procollagen 3, hydroxyproline, metalloproteinase 1, and telopetide.
2. Study the changes in liver fibrosis and other histological parameters of the disease: a. Proportion of patients in whom liver fibrosis does not progress, measured using the Ishak score, after treatment with simvastatin compared to placebo. Shift in the degree of liver fibrosis measured using the Ishak score, estimated with ordinal analysis. c. Liver fibrosis evaluated using the Metavir score (including evaluation with ordinal analysis), the EPOS score, and the "7-tier fibrosis staging system for ALD". d. Collagen proportional area in liver biopsies stained with Sirius Red and analyzed with Image J software. e. Histological parameters of chronic alcoholic liver disease: steatosis, neutrophil infiltration, Mallory hyaline, hepatocyte ballooning, etc.
3. Study the effect of simvastatin on the diversity and taxonomic composition of the gut microbiota using high-throughput sequencing.
4. Analyze the markers of systemic inflammation, immune response, bacterial translocation and endothelial dysfunction: a. Pro-inflammatory cytokines associated with alcoholic liver disease: IL-6, TNFα, and procalcitonin. b. Markers of bacterial translocation: bacterial lipopolysaccharide and lipopolysaccharide-binding protein. c. Markers of endothelial dysfunction: nitric oxide (NO), von Willebrand factor (vWF). d. Inflammatory profile of circulating immune cells: lymphocytes, monocytes, and neutrophils.
5. Analyze the relationship between muscle adverse effects and SLCO1B1 gene polymorphisms.
6. Describe the incidence of adverse effects and the safety of the treatment.

Conditions and MedDRA coding

Fibrosis liber, chronic liver disease, alcoholic liver disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Age ≥ 18 years
2. Chronic alcohol-related liver disease according to international guidelines (EASL, European Association for the Study of the Liver) and with data of significant liver fibrosis obtained in the diagnostic biopsy at the beginning of the study or in the last biopsy of the patient within 6 months prior to randomization. Significant liver fibrosis is defined by a score on the Ishak fibrosis scale of between 3 and 6.
3. Patients in the compensated chronic liver disease phase defined by the absence of clinical decompensations at the time of entering the study, with or without data of portal hypertension.
4. Women of childbearing potential must have a negative urine pregnancy test prior to study enrollment and agree to use highly effective contraceptive methods (combined oral pill, injectable or implanted contraceptive, intrauterine device / hormone delivery system intrauterine) during the study.

Exclusion criteria 24

1. Patients receiving statins or fibrates.
2. Patients with other etiologies of liver disease in addition to alcohol: hepatitis C, hepatitis B, autoimmune hepatitis, Wilson's disease, or hemochromatosis.
3. Patients in whom hepatitis C has been cured with antivirals in the 2 years prior to inclusion in the study.
4. Patients with a CK elevation of 50% or more above the upper limit of normal at the time of study inclusion
5. Gastrointestinal bleeding due to portal hypertension within the 12 months prior to inclusion in the study.
6. Clinical hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy, in the 12 months prior to inclusion in the study.
7. Patients in need of diuretic treatment in the previous 6 months to control ascites or hydrothorax.
8. Spontaneous bacterial peritonitis within 12 months prior to study enrollment.
9. Patients with a Child-Pugh score > 8 points.
10. Hepatocellular carcinoma of any stage.
11. Patients with known muscle disease.
12. Patients with previous rhabdomyolysis.
13. Patients being treated with strong CYP3A4 enzyme inhibitors (see section 5.2: Concomitant drugs, not allowed and allowed).
14. Patients being treated with drugs with possible interactions with simvastatin (see section 5.2: Concomitant drugs, not allowed and allowed).
15. Patients with a history of significant extrahepatic disease with poor short-term prognosis, including New York Heart Association Grade III / V congestive heart failure, GOLD COPD> 2, chronic kidney disease with serum creatinine> 2mg / dL or under therapy of kidney replacement.
16. Patients with extrahepatic malignancies, including solid tumors and hematologic malignancies.
17. Patients with a history or an increased risk of intestinal obstruction.
18. Pregnancy or breastfeeding.
19. Patients included in other clinical trials during the previous month.
20. Patients with mental disabilities, language barriers, poor social support or any other reason considered by the researcher as essential for adequate understanding, cooperation or compliance with the study.
21. Presence of data on alcoholic hepatitis in liver biopsy upon inclusion.
22. Patients with contraindications for statins.
23. Known hypersensitivity to simvastatin.
24. Refusal to sign the informed consent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline biopsy in the histological fibrosis score measured using the Ishak scale at 24 months.

Secondary endpoints 9

1. 1. Analyze the effect of simvastatin on liver fibrosis evaluated by noninvasive methods: a. Change in liver elasticity measured by transient liver elastography at 6, 12, 18 and 24 months. b. Change in liver elasticity measured by ERM at 24 months.
2. 1.c. Changes in serum markers and liver fibrosis scores validated for ALD and widely used in the general population: FIB-4 (Fibrosis Index for Liver Fibrosis) and ELF (Enhanced liver Fibrosis), pro-collagen 3, hydroxyproline, metalloproteinase 1 and telopeptide, at 6, 12, 18 y 24 months.
3. 2. Study the changes in liver fibrosis and other histological parameters of the disease: a. Absence of progression compared to the baseline biopsy in the histological fibrosis score measured using the Ishak scale at 24 months. b. Shift in the degree of liver fibrosis measured using the Ishak scale, estimated with ordinal analysis.
4. 2.c. Changes in liver fibrosis evaluated using the Metavir scale (including the shift evaluated with ordinal analysis), the EPOS scale, and the "7-tier fibrosis staging system for ALD" at 24 months. d. Change in the collagen proportional area in liver biopsies stained with Sirius red and analyzed with Image J software at 24 months. e. Changes in histological parameters of chronic alcoholic liver disease: steatosis, neutrophil infiltration, Mallory bodies, etc., at 24 months.
5. 3. Changes in the diversity and taxonomic composition of the gut microbiota through massive sequencing, at 24 months of treatment.
6. 4. Analyze the markers of systemic inflammation, immune response, bacterial translocation, and endothelial dysfunction: a. Change in the levels of pro-inflammatory cytokines associated with alcoholic liver disease: IL-6, TNFα, and procalcitonin; at 6, 12, 18, and 24 months. b. Change in the levels of bacterial translocation markers: bacterial lipopolysaccharide and lipopolysaccharide-binding protein; at 6, 12, 18, and 24 months.
7. 4.c. Change in the levels of endothelial dysfunction markers: nitric oxide (NO), von Willebrand factor (vWF); at 6, 12, 18, and 24 months. d. Change in the inflammatory profile of circulating immune cells: lymphocytes, monocytes, and neutrophils; at 24 months.
8. 5. Analyze the polymorphisms of the SLCO1B1 gene and their relationship with muscle toxicity.
9. 6. Incidence of adverse effects and safety of the treatment.

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacio De Recerca Clinic Barcelona-Institut D’Investigacions Biomediques August Pi I Sunyer

Sponsor organisation

Fundacio De Recerca Clinic Barcelona-Institut D’Investigacions Biomediques August Pi I Sunyer

Address

Calle Rosellon 149-153

City

Barcelona

Postcode

08036

Country

Spain

Scientific contact point

Organisation

Fundacio De Recerca Clinic Barcelona-Institut D’Investigacions Biomediques August Pi I Sunyer

Contact name

Dr. Pere Ginès

Public contact point

Organisation

Fundacio De Recerca Clinic Barcelona-Institut D’Investigacions Biomediques August Pi I Sunyer

Contact name

Dr. Pere Ginès

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 6 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