Anti-Fibrotic Effects of Losartan In Nash Evaluation Study

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

Official Title
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A Randomised, Controlled Trial of Losartan as an Anti-fibrotic Agent in Non-alcoholic Steatohepatitis

Conditions
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Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Losartan


Participation Criteria
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Eligibility Criteria
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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])

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Losartan, daily medication<br>50 milligrams Losartan to be taken orally daily | Drug: Losartan<br>* 50 milligrams to be taken orally, daily<br>* Other names: Losartan also known as Cozaar;|
| Placebo Comparator: Placebo<br>A matched placebo will be given for patients to take once daily | Drug: Losartan<br>* 50 milligrams to be taken orally, daily<br>* Other names: Losartan also known as Cozaar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Losartan, Liver fibrosis, Nonalcoholic steatohepatitis