Clinical trial NCT01051219: Anti-Fibrotic Effects of Losartan In Nash Evaluation Study
Official title: A Randomised, Controlled Trial of Losartan as an Anti-fibrotic Agent in Non-alcoholic Steatohepatitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Nonalcoholic Steatohepatitis
Keywords: Losartan
Liver fibrosis
Nonalcoholic steatohepatitis
Lead sponsor: Newcastle-upon-Tyne Hospitals NHS Trust
Sponsor class: OTHER
Collaborators: name: Newcastle University
First posted: 2010-01-18
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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 \[E464\])

Primary outcomes:
measure: 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
timeFrame: trial entry, end of study (2 years)
Secondary outcomes:
measure: Change in radiological (fibroscan) and serological (ELF) markers of fibrosis
timeFrame: trial entry, 48 weeks, 96 weeks
measure: change in NAFLD activity score (NAS)
timeFrame: trial entry, end of study
measure: comparison of "responder rate" - placebo versus intervention
timeFrame: trial entry, end of study
Other outcomes:
Locations:
city: Plymouth
country: United Kingdom
facility: Plymouth Hospitals NHS Trust
state: Devon
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Cambridge
country: United Kingdom
facility: Cambridge University NHS Foundation Trust
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool & Broadgreen University Hospital
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College (St Mary's Site)
city: London
country: United Kingdom
facility: St George's Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle Upon Tyne Hospitals NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Queens Medical Centre
Study officials:
affiliation: Newcastle University
name: Christopher P Day, PhD
role: STUDY_CHAIR
affiliation: Newcastle University
name: Derek Mann, PhD
role: STUDY_DIRECTOR
affiliation: Newcastle University
name: Stephen F Stewart, PhD
role: STUDY_DIRECTOR
affiliation: Newcastle University
name: Elaine McColl, PhD
role: STUDY_DIRECTOR
affiliation: Newcastle University
name: Ian N Steen, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.