Plain English Summary
Background and study aims
As many as 1 in 10 people have some form of liver disorder which can cause problems ranging from impaired quality of life to more serious complications including liver failure. Fibrosis is the accumulation of tough scar tissue in the liver, and occurs in patients with non-alcoholic steatohepatitis (NASH). The major feature of NASH is fat in the liver, along with inflammation and damage of the liver tissue. This can lead to permanent damage of the liver, which prevents it from functioning properly. Currently there are no available treatments aimed at slowing down or stopping the progression of fibrosis of the liver. Previous studies have demonstrated that drugs similar to Losartan help to reduce the inflammation. These studies would lead us to believe that Losartan will be effective in patients with NASH. This study aims to test Losartan in patients with fibrosis associated with NASH.
Who can participate?
Adults (both males and females, aged 18+) with fibrosis resulting from NASH.
What does the study involve?
Sometimes we need to find out how effective a study drug is by comparing two groups of patients with the same illness. We do this by giving the study tablet/capsule (Losartan) to one group and an identical looking tablet/capsule (the placebo), which contains inactive ingredients, to the other group. To try to make sure the groups are the same to start with, each patient is put into a group by chance (randomly – like tossing a coin). Neither you, your doctor, nor your spouse/family will know whether you are receiving Losartan or the placebo, as both will look exactly the same. We call this type of study a double-blind study. If your doctor needs to find out which treatment group you are in, then he or she may do so. You will take a study tablet/capsule once a day for up to two years. The study results will then be compared to see how effective the study drug is compared with the placebo. For the purposes of this study, you will attend your hospital outpatient department or research centre on nine occasions. On each of the nine occasions that you attend the hospital, your study assessment will take about 30 minutes, apart from your first visit which may take up to two hours. The assessments will be conducted by the research team, which includes a research doctor specializing in liver disease, as well as other trained research personnel. If you agree to be part of the study, you will be invited to sign the consent form before undergoing any research-related assessments. The sponsor of the study (Newcastle upon Tyne Hospitals NHS Foundation Trust) is currently in collaboration with GlaxoSmithKline who have requested the collection of extra blood samples to be collected at all of the visits, except visit three (week one). This will be explained to you by the Research Doctor, and you will be invited to participate in this separate voluntary study.
What are the possible benefits and risks of participating?
There may be no direct benefit to you from taking part. However, this study will help us to find out if Losartan is useful in slowing down, stopping or reversing liver fibrosis. We are unable to promise that the study will help you, but it may help patients in the future. There are no major disadvantages or risks in taking part in this study. Because we ask for some blood samples there is a small risk of bruising or discomfort at the injection site. A liver biopsy will be carried out at visit 8 (96 weeks). Up to one in three patients may experience some pain or discomfort following the biopsy. This may last two or three days. Usually a mild painkiller such as paracetamol is all that is need to treat this pain. Serious bleeding occurs in approximately one in 300 patients. This may require a blood transfusion or another procedure to stop it. Less than one in 1000 patients may have another organ punctured, such as lung, kidney or colon. This might cause pain or breathlessness, but would resolve itself without any further treatment. In less than one in 1000 patients, leakage of bile from the biopsy site into the abdomen may occur. This might cause pain in the abdomen but also usually resolves with no specific treatment. Patients with some conditions have an increased risk of infection after a liver biopsy. If we suspect that you have one of these conditions we will give you intravenous antibiotics before the biopsy. Slight discomfort may occur up to seven days after the biopsy, and you must inform your GP if this becomes severe or you develop swelling. Every effort will be made to keep you comfortable during this procedure. You will need to stay in hospital for six hours following the biopsy and possibly overnight after this procedure, but your doctor will discuss this with you prior to the procedure.
Where is the study run from?
Newcastle University (UK)
When is the study starting and how long is it expected to run for?
May 2011 to October 2014
Who is funding the study?
Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK)
Who is the main contact?
Jessica Qian
jessica.qian@newcastle.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Ms Jessica Qian
ORCID ID
Contact details
Trial Manager
Newcastle Clinical Trials Unit
Institute of Health and Society
Newcastle University
4th Floor William Leech Building
Medical School
Framlington Place
Newcastle upon Tyne
NE2 4HH
United Kingdom
+44 (0)191 222 7249
jessica.qian@newcastle.ac.uk
Type
Scientific
Additional contact
Ms Nicola Goudie
ORCID ID
Contact details
Assistant Trial Manager
Newcastle Clinical Trials Unit
Newcastle University
1-2 Claremont Terrace
Newcastle upon Tyne
NE2 4AE
United Kingdom
+44 (0)191 2087187
nicola.goudie@newcastle.ac.uk
Type
Scientific
Additional contact
Prof Christopher Paul Day
ORCID ID
Contact details
Institute of Cellular Medicine
Newcastle University
Faculty Office
Medical School
Newcastle upon Tyne
NE2 4HH
United Kingdom
+44 (0)191 2227003
chris.day@ncl.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
NCT01051219
Protocol/serial number
EME 08/43/15 Protocol Version V7.0, dated 09/05/12
Study information
Scientific title
A randomised controlled trial of losartan as an anti-fibrotic agent in non-alcoholic steatohepatitis
Acronym
FELINE (anti-Fibrotic Effects of Losartan In Nash Evaluation study)
Study hypothesis
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
Ethics approval
Sunderland Research Ethics Committee, 23/03/2010, ref: 10/H0904/8
Study design
Randomised parallel-group double-blind placebo-controlled study
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Fibrosis resulting from non-alcoholic steatohepatitis
Intervention
Treatment group: losartan orally, 50 mg capsule once a day for 24 months.
Control group: matched placebo orally, 1 capsule daily for 24 months.
Intervention type
Drug
Phase
Phase III
Drug names
Losartan
Primary outcome measure
Kleiner fibrosis score, based on histological fibrosis stage at trial entry and end of study (96 weeks)
Secondary outcome measures
1. Measurement of change in fibroscan score performed at trial entry, 48 weeks and end of study
2. Serological (Enhanced Liver Fibrosis test [ELF™ test]) markers of fibrosis performed at trial entry, 48 weeks and end of study
3. Change in non-alcoholic fatty liver disease (NAFLD) activity score (NAS) from baseline, determined by liver biopsy at trial entry and end of study
Overall trial start date
01/05/2011
Overall trial end date
01/10/2014
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Current inclusion criteria as of 16/06/2011:
Adults (both males and females, aged 18+) with steatohepatitis and fibrosis (Kleiner F1-F3), resulting from non-alcoholic fatty liver disease
Previous inclusion criteria:
Adults (both males and females, aged 18+) with fibrosis resulting from non-alcoholic steatohepatitis.
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
214 (107 in treatment group, 107 in control group)
Participant exclusion criteria
Current exclusion criteria as of 09/07/2012:
1. Refusal or inability (lack of capacity) to give informed consent
2. Average alcohol ingestion >21 units/week (males) or >14 units/week (females)
3. History or presence of Type 1 diabetes mellitus
4. Haemoglobin A1C >15.0
5. Other causes of chronic liver disease or hepatic steatosis
6. Any contra-indication to liver biopsy
7. History of or planned gastrointestinal bypass surgery
8. Hepatocellular carcinoma
9. Previous liver transplantation
10. Recent significant weight loss (>5% total body weight within last 6 months)
11. Electrolyte disturbance: potassium level outside the normal (local) range.
12. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >10 x upper limit of normal (ULN) at screening
13. 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.
14. 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.
15. Intolerance of angiotensin receptor blockers (ARBs) or presence of multiple allergic reactions to drugs
16. Use of angiotensin-converting enzyme (ACE) inhibitor or ARB in previous year
17. Hypotension (systolic <100, diastolic <60)
18. Renal failure (Cr >130)
19. Participation in any clinical study of an investigational agent within 30 days or five half-lives of the investigational product, whichever is longer
20. Presence of clinically relevant cardiovascular, pulmonary, gastro-intestinal, 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
21. Presence or history of cancer within the past 5 years with exception of adequately treated localised basal cell carcinoma of the skin, in situ cervical carcinoma or solid malignancy surgically excised in toto without recurrence for five years
22. 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)
23. Known allergy or sensitivity to losartan or its excipients (microcrystalline cellulose [E460]; lactose monohydrate; pregelaatinized maize starch; magnesium stearate [E572]; hydroxypropyl cellulose [E463]; hypromellose [E464])
Previous exclusion criteria until 09/07/2012:
4. Haemoglobin A1C>9.0
14. Recent (within 3 months of baseline liver biopsy and screening visit) change in anti-diabetes treatment or change in dose or regimen, or introduction of Vitamin E or C, betaine, s-adenosyl methionine, ursodeoxycholic acid, silymarin, fibrate, pentoxifylline, orlistat, sibutramine or rimonabant.
Previous exclusion criteria:
4. Haemoglobin A1C >8.5
12. 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)
13. Recent (within 3 months of baseline liver biopsy and screening visit) change in anti-diabetes treatment
14. Recent (within 6 months of baseline liver biopsy and screening visit) or concomitant use of pioglitazone, fluconazole, rifampicin or any drug contra-indicated in the losartan SmPC
15. Recent (within 3 months of baseline liver biopsy and screening visit) change in dose/regimen or introduction of vitamin E or C, betaine, s-adenosyl methionine, ursodeoxycholic acid, silymarin, fibrate or pentoxifylline
20. Decompensated cirrhosis Childs-Pugh Class B or C (score >6)
Recruitment start date
30/06/2011
Recruitment end date
18/10/2012
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Birmingham University Hospital NHS Foundation Trust
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
Trial participating centre
Cambridge University NHS Trust
Addenbrooke's Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Trial participating centre
Guy's & St Thomas's NHS Foundation Trust
Westminster Bridge Road
London
SE1 7EH
United Kingdom
Trial participating centre
Imperial College NHS Trust
St Mary’s Hospital
Praed Street
London
W2 1NY
United Kingdom
Trial participating centre
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Clinical Research Facility
Level 6, Leazes Wing
Newcastle upon Tyne
NE1 4LP
United Kingdom
Trial participating centre
Nottingham University Hospitals NHS Trust
Queens Medical Centre Campus
Derby Road
Nottingham
NG7 2UH
United Kingdom
Trial participating centre
Plymouth Hospitals NHS Foundation Trust
Derriford Hospital
Derriford Road
Crowhill
Plymouth
PL6 8DH
United Kingdom
Trial participating centre
St George's Healthcare NHS Trust
Dept. of Gastroenterology and Hepatology
St George's Hospital
Blackshaw Road
London
SW17 0QT
United Kingdom
Trial participating centre
Derby Hospitals NHS Foundation Trust
Royal Derby Hospital
Uttoxeter Road
Derby
DE22 3NE
United Kingdom
Trial participating centre
Royal Liverpool & Broadgreen University Hospitals NHS Trust
Royal Liverpool University Hospital
4th Floor Linda McCartney Centre
R&D Dept
Prescot Street
Liverpool
L7 8XP
United Kingdom
Sponsor information
Organisation
Newcastle upon Tyne Hospitals NHS Foundation Trust (UK)
Sponsor details
Joint Research Office
Level 6
Leazes Wing
Royal Victoria Infrimary
Queen Victoria Road
Newcastle upon Tyne
NE1 4LP
United Kingdom
Sponsor type
Government
Website
http://www.newcastle-hospitals.org.uk/about-us/staff-information_research-development.aspx
Funders
Funder type
Government
Funder name
Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: EME 08/43/15)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
To be confirmed at a later date
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2017 results in: https://www.ncbi.nlm.nih.gov/pubmed/28419124