Nonalcoholic SteatohepatitisPhase 3FELINENCT01051219
Anti-Fibrotic Effects of Losartan In Nash Evaluation Study
A Phase 3 study testing Losartan in people with Nonalcoholic Steatohepatitis, run by Newcastle-upon-Tyne Hospitals NHS Trust at 10 sites in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Nonalcoholic Steatohepatitis
- What is being tested?
- Losartan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 45 participants
- Where
- 10 sitesUnited Kingdom
- Study dates
- May 2011to Dec 2014
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adults (both males and females, aged 18+) with steatohepatitis and fibrosis (Kleiner F1-F3), resulting from non-alcoholic fatty liver disease.
Who cannot join
- 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
Show all 23Show fewer
- 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])
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
United Kingdom10 sites
Queen Elizabeth Hospital
Birmingham, B15 2TH
Cambridge University NHS Foundation Trust
Cambridge, CB2 0QQ
Royal Derby Hospital
Derby
Royal Liverpool & Broadgreen University Hospital
Liverpool
Guy's and St Thomas' NHS Foundation Trust
London, SE1 7EH
Imperial College (St Mary's Site)
London, SW7 2AZ
St George's Hospital
London
Newcastle Upon Tyne Hospitals NHS Foundation Trust
Newcastle upon Tyne, NE7 7DN
Queens Medical Centre
Nottingham, NG7 2UH
Plymouth Hospitals NHS Trust
Plymouth, Devon, PL6 8DH
About this study
Official title: A Randomised, Controlled Trial of Losartan as an Anti-fibrotic Agent in Non-alcoholic Steatohepatitis
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:
Read more
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
- Conditions
- Nonalcoholic Steatohepatitis
- Being tested
- Losartan
- Keywords
- Losartan, Liver fibrosis, Nonalcoholic steatohepatitis
- Medical subject headings
- Non-alcoholic Fatty Liver Disease, Liver Cirrhosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LosartanDrug
Also called Losartan also known as Cozaar
50 milligrams to be taken orally, daily
| Study group | Role | What they receive |
|---|---|---|
| Losartan, daily medication | Active comparator | 50 milligrams Losartan to be taken orally daily Receives: Drug: Losartan |
| Placebo | Placebo comparator | A matched placebo will be given for patients to take once daily Receives: Drug: Losartan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: trial entry, end of study (2 years)
Secondary outcomes (3)
Change in radiological (fibroscan) and serological (ELF) markers of fibrosis
Measured: trial entry, 48 weeks, 96 weeks
change in NAFLD activity score (NAS)
Measured: trial entry, end of study
comparison of "responder rate" - placebo versus intervention
Measured: trial entry, end of study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jan 2010 (estimated)
- Study startMay 2011
- Primary completionNov 2014
- Study completionDec 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Nonalcoholic SteatohepatitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- Newcastle-upon-Tyne Hospitals NHS Trust
- Sponsor type
- University, hospital or other
- Collaborators
- Newcastle University
- Responsible party
- Sponsor
- Investigators
- Christopher P Day, PhD, Study chair, Newcastle UniversityDerek Mann, PhD, Study director, Newcastle UniversityStephen F Stewart, PhD, Study director, Newcastle UniversityElaine McColl, PhD, Study director, Newcastle UniversityIan N Steen, PhD, Study director, Newcastle University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01051219
- Sponsor's protocol ID
- EME-08/43/15
- Other IDs
- ISRCTN
- Acronym
- FELINE
- Status last verified
- Oct 2015
- First submitted
- 15 Jan 2010
- Last updated
- 7 Oct 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 15915461Newton 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.
PubMed 18270241Lindor 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.
PubMed 14999696Adams 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.
PubMed 15629518Adams 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.
PubMed 16012941Wright 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.
PubMed 11522753Watson 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.
PubMed 18279996Oakley 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.
PubMed 15633128Bataller 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.
PubMed 12851877Bataller 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.
PubMed 15841463
Study at a glance
From the registry record, last updated by the sponsor on 7 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised, Controlled Trial of Losartan as an Anti-fibrotic Agent in Non-alcoholic Steatohepatitis
- ClinicalTrials.gov ID
- NCT01051219
- Acronym / sponsor ID
- FELINE / EME-08/43/15
- Conditions
- Nonalcoholic Steatohepatitis
- Keywords
- Losartan, Liver fibrosis, Nonalcoholic steatohepatitis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 45 participants (actual)
- Lead sponsor
- Newcastle-upon-Tyne Hospitals NHS TrustUniversity, hospital or other
- Collaborators
- Newcastle University
- Study start
- May 2011
- Primary completion
- Nov 2014 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 18 Jan 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Losartan, daily medication | Active comparator | Drug: Losartan50 milligrams Losartan to be taken orally daily |
| Placebo | Placebo comparator | Drug: LosartanA matched placebo will be given for patients to take once daily |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Adults (both males and females, aged 18+) with steatohepatitis and fibrosis (Kleiner F1-F3), resulting from non-alcoholic fatty liver disease.
Key exclusion criteria (23 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LosartanAlso: Losartan also known as Cozaar50 milligrams to be taken orally, daily | Drug | Losartan, daily medication, Placebo |
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
Time frame: trial entry, end of study (2 years)
3 secondary outcomes
Change in radiological (fibroscan) and serological (ELF) markers of fibrosis
Time frame: trial entry, 48 weeks, 96 weeks
change in NAFLD activity score (NAS)
Time frame: trial entry, end of study
comparison of "responder rate" - placebo versus intervention
Time frame: trial entry, end of study
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Oct 2015.
- Background: PubMed 15915461Kleiner 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.
- Background: PubMed 18270241Newton 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.
- Background: PubMed 14999696Lindor 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.
- Background: PubMed 15629518Adams 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.
- Background: PubMed 16012941Adams 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.
- Background: PubMed 11522753Wright 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.
- Background: PubMed 18279996Watson 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.
- Background: PubMed 15633128Oakley 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.
- Background: PubMed 12851877Bataller 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.
- Background: PubMed 15841463Bataller 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Christopher P Day, PhD study chair
Newcastle University
Derek Mann, PhD study director
Newcastle University
Stephen F Stewart, PhD study director
Newcastle University
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Losartan in people with Nonalcoholic Steatohepatitis, run by Newcastle-upon-Tyne Hospitals NHS Trust at 10 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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 (time frame: trial entry, end of study (2 years)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01051219, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Oct 2015.