Nonalcoholic Steatohepatitis | Anti-Fibrotic Effects of Losartan In Nash Evaluation Study
Nonalcoholic Steatohepatitis research study
What is the primary objective of this study?
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
Who is eligible to participate?
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])
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:Losartan50 milligrams to be taken orally, daily
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
Losartan, daily medication50 milligrams Losartan to be taken orally daily
PlaceboA matched placebo will be given for patients to take once daily
Start Date: May 2011
Completed Date: December 2014
Phase: Phase 3
Primary Outcome: 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
Secondary Outcome: Change in radiological (fibroscan) and serological (ELF) markers of fibrosis
Study sponsors, principal investigator, and references
Principal Investigator: Christopher P Day, PhD
Lead Sponsor: Newcastle-upon-Tyne Hospitals NHS Trust
Collaborator: Newcastle University
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.