Anti-Fibrotic Effects of Losartan In Nash Evaluation Study

NCT ID: NCT01051219

Last Updated: 2015-10-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-05-31
• Study Completion Date: 2014-12-31

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. That the safety profile of the angiotensin receptor blocker (losartan) in this patient population is acceptable

2. That losartan can prevent clinical deterioration in non-alcoholic fatty liver disease

3. That serum, radiological and histological markers of fibrosis correlate in these patients over a 24 month period

Conditions

Nonalcoholic Steatohepatitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Losartan, daily medication

50 milligrams Losartan to be taken orally daily

Group Type: ACTIVE_COMPARATOR

Losartan

Intervention Type: DRUG

50 milligrams to be taken orally, daily

Placebo

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

Group Type: PLACEBO_COMPARATOR

Losartan

Intervention Type: DRUG

50 milligrams to be taken orally, daily

Interventions

Losartan

50 milligrams to be taken orally, daily

Intervention Type: DRUG

Other Intervention Names

Losartan also known as Cozaar

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

• 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
• Use of angiotensin-converting enzyme (ACE) inhibitor or ARB in previous year
• Hypotension (systolic <100, diastolic <60)
• Renal failure (Cr >130)
• Participation in any clinical study of an investigational agent within 30 days or five half-lives of the investigational product, whichever is longer
• Presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, renal, hepatic, metabolic, haematological, neurological, psychiatric, systemic, ocular, gynaecologic or any acute infectious disease or signs of acute illness that, in the opinion of the investigator, might compromise the patient's safe participation in the trial
• Presence or history of cancer within the past 5 years with exception of adequately treated localized basal cell carcinoma of the skin, in situ cervical carcinoma or solid malignancy surgically excised in toto without recurrence for five years
• Women of child-bearing potential not protected by effective contraceptive method of birth control or surgical sterilization and/or who are unwilling or unable to be tested for pregnancy (Pregnancy status will be checked by serum pregnancy testing before initiation of study treatment and by urine pregnancy testing during the trial)
• Known allergy or sensitivity to losartan or its excipients (microcrystalline cellulose [E460]; lactose monohydrate; pregelitanized maize starch; magnesium stearate [E572]; hydroxypropyl cellulose [E463]; hypromellose [E464])

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Newcastle University

OTHER

Sponsor Role: collaborator

Newcastle-upon-Tyne Hospitals NHS Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christopher P Day, PhD

Role: STUDY_CHAIR

Newcastle University

Derek Mann, PhD

Role: STUDY_DIRECTOR

Newcastle University

Stephen F Stewart, PhD

Role: STUDY_DIRECTOR

Newcastle University

Elaine McColl, PhD

Role: STUDY_DIRECTOR

Newcastle University

Ian N Steen, PhD

Role: STUDY_DIRECTOR

Newcastle University

Locations

Plymouth Hospitals NHS Trust

Plymouth, Devon, United Kingdom

Queen Elizabeth Hospital

Birmingham, , United Kingdom

Cambridge University NHS Foundation Trust

Cambridge, , United Kingdom

Royal Derby Hospital

Derby, , United Kingdom

Royal Liverpool & Broadgreen University Hospital

Liverpool, , United Kingdom

Guy's and St Thomas' NHS Foundation Trust

London, , United Kingdom

Imperial College (St Mary's Site)

London, , United Kingdom

St George's Hospital

London, , United Kingdom

Newcastle Upon Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, , United Kingdom

Queens Medical Centre

Nottingham, , United Kingdom

Countries

United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 15915461 (View on PubMed)

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.

Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

PMID: 11522753 (View on PubMed)

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.

Reference Type: BACKGROUND

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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.

Reference Type: BACKGROUND

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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.

Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Other Identifiers

ISRCTN

Identifier Type: REGISTRY

Identifier Source: secondary_id

EME-08/43/15

Identifier Type: -

Identifier Source: org_study_id