Statins for Prevention of Disease Progression and Hospitalization in Liver Cirrhosis

NCT04072601 | Terminated Phase 4 DMC

• 1 other identifier: STATLiver2019
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 1

Brief Summary

In a randomized, doubleblind and placebo-controlled trial we assess both clinical and cellular effects of atorvastatin in patients with liver cirrhosis. 162 participants will be allocated to atorvastatin 10-20 mg or placebo for 18 months. Clinical outcomes of survival, hospitalizations and safety will be evaluated. Also, the trial will investigate cellular functions in the liver by mass spectrometry proteomics, and single cell transcriptomics as well as exploring atorvastatin effects on different fenotypes by metagenomics.

Conditions

Liver Cirrhoses

Outcome Measures

Primary Outcomes (2)

• Composite endpoint of numbers of death or liver transplantation

  1.5 years

• Number of hospitalizations with liver related complications

  1.5 years

Secondary Outcomes (14)

• Number of adverse events

  1.5 years (18 months)

• Number of Patients developing decompensation of liver cirrhosis

  1.5 and 5 years

• Inflammation and macrophage activation

  0.5 and 1.5 years

• Change in clinical score

  0.5, 1.5 years

• Numbers of episodes of decompensation

  1.5 and 5 years

Study Arms (2)

Atorvastatin

EXPERIMENTAL

Atorvastatin 10-20 mg for 18 months of treatment. Start dose is 10 mg, adjusted to 20 mg after 15-30 days if no sideeffects occurs.

Drug: Atorvastatin 10mg

Control

PLACEBO COMPARATOR

Placebo of atorvastatin 10 mg, 1-2 tablets for 18 months of treatment. Start dose is 1 tablet (10 mg placebo), adjusted to 2 tablets (20 mg placebo) after 15-30 days if no side effects occurs.

Drug: Placebo oral tablet

Interventions

Placebo oral tablet DRUG

Lactose monohydrate 50 mg, potato starch 45 mg, Gelatine 1,2 mg, Magnesium stearate 0,5, Talc 4,5 mg

Control

Atorvastatin 10mg DRUG

Tablet, can be adjusted to 2 tablets if tolerated

Atorvastatin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients in the age of 18 to 80 years
• Patients with liver cirrhosis, diagnosed by liver biopsy or ultrasound or CT scan of the liver and clinical biochemistry compatible with cirrhosis within the past 3 months.
• In women, documented absence of pregnancy and unless in menopause commitment to use adequate contraception.
• Clinically significant portal hypertension with a hepatic venous pressure gradient measured by liver vein catheterization \>10 mmHg.
• Ability to read and understand project information in Danish and give written, informed consent.

You may not qualify if:

• People treated with statins within the last year.
• People with liver cirrhosis, with a clinically verified infection (standard biochemistry, culture) within the last four weeks.
• Pregnancy or lactation.
• Hepatocellular carcinoma
• HIV infection and treatment with protease inhibitors
• People in whom the clinician and investigators may have reason to doubt compliance to trial medication
• Clinical and biochemical signs of hepato-renal syndrome defined by current guidelines (EASL) within the last 14 days
• A MELD score above 23, or Child-Pugh score higher than 13.
• Hepatic encephalopathy grade 2 or higher

Sponsors & Collaborators

• Copenhagen University Hospital, Hvidovre: lead
• University of Copenhagen: collaborator
• Aarhus University Hospital: collaborator
• Rigshospitalet, Denmark: collaborator

Study Sites (1)

Gastro Unit, medical Division, University Hospital Hvidovre

Hvidovre, Danmark, 2650, Denmark

Location

Related Publications (10)

• Lefer DJ. Statins as potent antiinflammatory drugs. Circulation. 2002 Oct 15;106(16):2041-2. doi: 10.1161/01.cir.0000033635.42612.88. No abstract available.

  PMID: 12379569 BACKGROUND

• McGirt MJ, Lynch JR, Parra A, Sheng H, Pearlstein RD, Laskowitz DT, Pelligrino DA, Warner DS. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke. 2002 Dec;33(12):2950-6. doi: 10.1161/01.str.0000038986.68044.39.

  PMID: 12468796 BACKGROUND

• Chong LW, Hsu YC, Lee TF, Lin Y, Chiu YT, Yang KC, Wu JC, Huang YT. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells. BMC Gastroenterol. 2015 Feb 15;15:22. doi: 10.1186/s12876-015-0248-8.

  PMID: 25886887 BACKGROUND

• Zafra C, Abraldes JG, Turnes J, Berzigotti A, Fernandez M, Garca-Pagan JC, Rodes J, Bosch J. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology. 2004 Mar;126(3):749-55. doi: 10.1053/j.gastro.2003.12.007.

  PMID: 14988829 BACKGROUND

• Abraldes JG, Albillos A, Banares R, Turnes J, Gonzalez R, Garcia-Pagan JC, Bosch J. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology. 2009 May;136(5):1651-8. doi: 10.1053/j.gastro.2009.01.043. Epub 2009 Jan 24.

  PMID: 19208350 BACKGROUND

• Cash WJ, O'Neill S, O'Donnell ME, McCance DR, Young IS, McEneny J, McDougall NI, Callender ME. Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis. Liver Int. 2013 Sep;33(8):1166-74. doi: 10.1111/liv.12191. Epub 2013 May 15.

  PMID: 23672463 BACKGROUND

• Pollo-Flores P, Soldan M, Santos UC, Kunz DG, Mattos DE, da Silva AC, Marchiori RC, Rezende GF. Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: A randomized controlled trial. Dig Liver Dis. 2015 Nov;47(11):957-63. doi: 10.1016/j.dld.2015.07.156. Epub 2015 Aug 6.

  PMID: 26321186 BACKGROUND

• Abraldes JG, Villanueva C, Aracil C, Turnes J, Hernandez-Guerra M, Genesca J, Rodriguez M, Castellote J, Garcia-Pagan JC, Torres F, Calleja JL, Albillos A, Bosch J; BLEPS Study Group. Addition of Simvastatin to Standard Therapy for the Prevention of Variceal Rebleeding Does Not Reduce Rebleeding but Increases Survival in Patients With Cirrhosis. Gastroenterology. 2016 May;150(5):1160-1170.e3. doi: 10.1053/j.gastro.2016.01.004. Epub 2016 Jan 14.

  PMID: 26774179 BACKGROUND

• Kalinowski L, Dobrucki LW, Brovkovych V, Malinski T. Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation. 2002 Feb 26;105(8):933-8. doi: 10.1161/hc0802.104283.

  PMID: 11864921 RESULT

• Kimer N, Gronbaek H, Fred RG, Hansen T, Deshmukh AS, Mann M, Bendtsen F. Atorvastatin for prevention of disease progression and hospitalisation in liver cirrhosis: protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open. 2020 Jan 23;10(1):e035284. doi: 10.1136/bmjopen-2019-035284.

  PMID: 31980514 DERIVED

Related Links

• @Nkimer is a twitter account posting progress on the StatLiver trial

MeSH Terms

Interventions

Atorvastatin

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Study Officials

• Thit M Kronborg, MD

  Gastro Unit, Hvidovre University Hospital

  PRINCIPAL INVESTIGATOR

• Flemming Bendtsen, DmSci

  Gastro Unit, Hvidovre University Hospital

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Allocation and randomisation is blinded. Participants are only identified by randomisation number (no group names) Allocation ratio is 1:1 All personnel and participants are blinded through the study period. All outcome assessors are blinded to treatment, and initial data analysis is performed blinded.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD, Clinician Researcher

Model Details: Part One: Enrolment of 48 participants. Evaluation of safety, resources and recruitment. If adequate, Part Two: Enrolment up to 162 participants.

Study Record Dates

• First Submitted: June 5, 2019
• First Posted: August 28, 2019
• Study Start: November 8, 2019
• Primary Completion: July 31, 2022
• Study Completion: January 10, 2023
• Last Updated: January 13, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data will be stored for up to 10 years after completion of the trial, depending on approval from Danish Health Authorities, Scientific Ethics Comittee and the Danish Data Protection Regulation.
• Access Criteria: upon request

Locations

DK (1)