Anti-Fibrotic Effects of Losartan In Nash Evaluation Study

NCT01051219 | Completed Phase 3 DMC

• 2 other identifiers: EME-08/43/15ISRCTN
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 10

Brief Summary

This is a randomized, controlled trial to determine whether Losartan is effective at slowing down, halting or reversing liver fibrosis in patients with non-alcoholic steatohepatitis (NASH). Liver fibrosis is the accumulation of tough, fibrous scar tissue in the liver which occurs in patients with NASH. NASH resembles alcoholic liver disease, but occurs in people who drink little or no alcohol. The major feature in NASH is fat in the liver, along with inflammation and damage, which may lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer able to function properly. Primary hypothesis: That losartan is superior to placebo in reversing, slowing down or halting fibrosis in patients with non-alcoholic fatty liver disease, after 24 months of treatment. Secondary hypothesis:

1. 1.That the safety profile of the angiotensin receptor blocker (losartan) in this patient population is acceptable
2. 2.That losartan can prevent clinical deterioration in non-alcoholic fatty liver disease
3. 3.That serum, radiological and histological markers of fibrosis correlate in these patients over a 24 month period

Conditions

Nonalcoholic Steatohepatitis

Keywords

Losartan; Liver fibrosis; Nonalcoholic steatohepatitis

Outcome Measures

Primary Outcomes (1)

• The primary outcome will be change in Kleiner fibrosis score, [Kleiner DE et al Hepatology 2005], based on histological fibrosis stage (as judged by two independent blinded histopathologists from liver biopsies), from pre-treatment to end-of-study

  trial entry, end of study (2 years)

Secondary Outcomes (3)

• Change in radiological (fibroscan) and serological (ELF) markers of fibrosis

  trial entry, 48 weeks, 96 weeks

• change in NAFLD activity score (NAS)

  trial entry, end of study

• comparison of "responder rate" - placebo versus intervention

  trial entry, end of study

Study Arms (2)

Losartan, daily medication

ACTIVE COMPARATOR

50 milligrams Losartan to be taken orally daily

Drug: Losartan

Placebo

PLACEBO COMPARATOR

A matched placebo will be given for patients to take once daily

Drug: Losartan

Interventions

Losartan DRUG

50 milligrams to be taken orally, daily

Also known as: Losartan also known as Cozaar

Losartan, daily medication; Placebo

Eligibility Criteria

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

You may qualify if:

• Adults (both males and females, aged 18+) with steatohepatitis and fibrosis (Kleiner F1-F3), resulting from non-alcoholic fatty liver disease.

You may not qualify if:

• Refusal or inability (lack of capacity) to give informed consent
• Average alcohol ingestion \>21 units/week (males) or \>14 units/week (females)
• History or presence of Type 1 diabetes mellitus
• Haemoglobin A1C \>15.0
• Other causes of chronic liver disease or hepatic steatosis
• Any contra-indication to liver biopsy
• History of, or planned, gastrointestinal bypass surgery
• Hepatocellular carcinoma
• Previous liver transplantation
• Recent significant weight loss (\>5% total body weight within last 6 months)
• Electrolyte disturbance: potassium level outside the normal (local) range
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>10 x upper limit of normal (ULN) at screening
• Recent (within 6 months of baseline liver biopsy and screening visit) or concomitant use of agent known to cause hepatic steatosis (corticosteroids, amiodarone, methotrexate, tamoxifen, tetracycline, high dose oestrogens, valproic acid), or concomitant use of pioglitazone, fluconazole, rifampicin or any drug contra-indicated in the Losartan SmPC
• Introduction of metformin, glitazones, a GLP-1 agonist, Vitamin E or C, betaine, s-adenosyl methionine, ursodeoxycholic acid, silymarin, fibrate, pentoxifylline, orlistat, sibutramine or rimonabant within 3 months of baseline liver biopsy and screening visit
• Intolerance of angiotensin receptor blockers (ARBs) or presence of multiple allergic reactions to drugs

Sponsors & Collaborators

• Newcastle-upon-Tyne Hospitals NHS Trust: lead
• Newcastle University: collaborator

Study Sites (10)

Plymouth Hospitals NHS Trust

Plymouth, Devon, PL6 8DH, United Kingdom

Location

Queen Elizabeth Hospital

Birmingham, B15 2TH, United Kingdom

Location

Cambridge University NHS Foundation Trust

Cambridge, CB2 0QQ, United Kingdom

Location

Royal Derby Hospital

Derby, United Kingdom

Location

Royal Liverpool & Broadgreen University Hospital

Liverpool, United Kingdom

Location

Guy's and St Thomas' NHS Foundation Trust

London, SE1 7EH, United Kingdom

Location

Imperial College (St Mary's Site)

London, SW7 2AZ, United Kingdom

Location

St George's Hospital

London, United Kingdom

Location

Newcastle Upon Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Queens Medical Centre

Nottingham, NG7 2UH, United Kingdom

Location

Related Publications (10)

• Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005 Jun;41(6):1313-21. doi: 10.1002/hep.20701.

  PMID: 15915461 BACKGROUND

• Newton JL, Jones DE, Henderson E, Kane L, Wilton K, Burt AD, Day CP. Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance. Gut. 2008 Jun;57(6):807-13. doi: 10.1136/gut.2007.139303. Epub 2008 Feb 12.

  PMID: 18270241 BACKGROUND

• Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004 Mar;39(3):770-8. doi: 10.1002/hep.20092.

  PMID: 14999696 BACKGROUND

• Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005 Jan;42(1):132-8. doi: 10.1016/j.jhep.2004.09.012.

  PMID: 15629518 BACKGROUND

• Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005 Jul;129(1):113-21. doi: 10.1053/j.gastro.2005.04.014.

  PMID: 16012941 BACKGROUND

• Wright MC, Issa R, Smart DE, Trim N, Murray GI, Primrose JN, Arthur MJ, Iredale JP, Mann DA. Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology. 2001 Sep;121(3):685-98. doi: 10.1053/gast.2001.27188.

  PMID: 11522753 BACKGROUND

• Watson MR, Wallace K, Gieling RG, Manas DM, Jaffray E, Hay RT, Mann DA, Oakley F. NF-kappaB is a critical regulator of the survival of rodent and human hepatic myofibroblasts. J Hepatol. 2008 Apr;48(4):589-97. doi: 10.1016/j.jhep.2007.12.019. Epub 2008 Jan 31.

  PMID: 18279996 BACKGROUND

• Oakley F, Meso M, Iredale JP, Green K, Marek CJ, Zhou X, May MJ, Millward-Sadler H, Wright MC, Mann DA. Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology. 2005 Jan;128(1):108-20. doi: 10.1053/j.gastro.2004.10.003.

  PMID: 15633128 BACKGROUND

• Bataller R, Sancho-Bru P, Gines P, Lora JM, Al-Garawi A, Sole M, Colmenero J, Nicolas JM, Jimenez W, Weich N, Gutierrez-Ramos JC, Arroyo V, Rodes J. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology. 2003 Jul;125(1):117-25. doi: 10.1016/s0016-5085(03)00695-4.

  PMID: 12851877 BACKGROUND

• Bataller R, Gabele E, Parsons CJ, Morris T, Yang L, Schoonhoven R, Brenner DA, Rippe RA. Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct-ligated rats. Hepatology. 2005 May;41(5):1046-55. doi: 10.1002/hep.20665.

  PMID: 15841463 BACKGROUND

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Liver Cirrhosis

Interventions

Losartan

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Study Officials

• Christopher P Day, PhD

  Newcastle University

  STUDY CHAIR

• Derek Mann, PhD

  Newcastle University

  STUDY DIRECTOR

• Stephen F Stewart, PhD

  Newcastle University

  STUDY DIRECTOR

• Elaine McColl, PhD

  Newcastle University

  STUDY DIRECTOR

• Ian N Steen, PhD

  Newcastle University

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 15, 2010
• First Posted: January 18, 2010
• Study Start: May 1, 2011
• Primary Completion: November 1, 2014
• Study Completion: December 1, 2014
• Last Updated: October 7, 2015

Record last verified: 2015-10

Locations

GB (10)