Treatment of Non Alcoholic Fatty Liver Disease With n-3 Fatty Acids

NCT ID: NCT00760513

Last Updated: 2019-10-25

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

103 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-11-01

Study Completion Date

2018-11-29

Brief Summary

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Non alcoholic fatty liver disease (NAFLD) imposes a high and increasing burden on the NHS, yet there is presently no licensed treatment or validated approach to management. NAFLD predisposes to increased risk of type 2 diabetes, increased risk of cardiovascular disease and may progress to chronic irreversible liver disease.

In NAFLD patients, the investigators will test the hypothesis that treatment with long chain n-3 fatty acid supplementation for 18 months favourably influences bio-markers for NAFLD and risk factors for cardiovascular disease and type 2 diabetes.

Detailed Description

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We will recruit people with NAFLD who have been diagnosed as part of their NHS care with having this condition. At present there is no treatment for this condition. Over time a proportion of people with NAFLD.

Purpose and design

We are asking the research question ' Does treatment with purified long chain n-3 fatty acids (purified fish oil) improve non alcoholic fatty liver disease and risk factors for heart disease and type 2 (adult) diabetes that are strongly linked to this liver condition?'

Presently there is no treatment for this liver condition. Research evidence suggests that purified long chain n-3 fatty acids might be beneficial for this condition.

To address this research question we want to undertake a randomised double blind placebo controlled trial recruiting people who have been diagnosed with a liver biopsy as having the liver condition.

A protocol change that were approved during in the course of the study in October 2011.

In the protocol, we have deleted information regarding liver biopsy that was to be offered at the end of the study.

Having collated volunteer opinion and local consultant opinion, whereas a high proportion of volunteers were happy to undergo a follow up liver biopsy, our local hepatologists now consider that in 2011, the small risk of morbidity and mortality of volunteers undergoing liver biopsy is unacceptable, within the context of a research study. Their opinions have changed since 2008 when the initial LREC approval was granted.

Liver biopsy was always an optional extra and would only have been undertaken in a subgroup of the volunteers. Therefore, removal of liver biopsy from the protocol does not affect the validity of the study to test effects of the n-3 fatty acid intervention on biomarkers and liver fat in people with non alcoholic fatty liver disease.

Besides removal of liver biopsy from the protocol, we have clarified in the protocol, the end points of the study and numbers randomised to either n-3 fatty acid or placebo (n=100, as always intended). We have also made it clear in the amendment that measurement of liver fat is also a primary outcome of the study. (We already have permission to undertake this test but it was uncertain when the study was approved that we would have sufficient funding for this expensive test and it was originally not a primary outcome).

We have therefore added a power calculation (and cited the relevant literature) to show that with a sample size of n=100 people, based upon the known treatment effects of n-3 fatty acids on liver fat, we have acceptable power to detect the predicted decrease in this outcome with treatment.

Conditions

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Non-Alcoholic Fatty Liver Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Investigators

Study Groups

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Omega 3 fatty acid (fish oil)

OMACOR (alternative name: Lovaza) 4 grammes daily, oral capsule

Group Type ACTIVE_COMPARATOR

OMACOR

Intervention Type DRUG

4 grammes daily, oral capsule

dummy pill

4 grammes daily, oral capsule (olive oil)

Group Type PLACEBO_COMPARATOR

Placebo oral capsule

Intervention Type DRUG

4 grammes daily, oral capsule (olive oil)

Interventions

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OMACOR

4 grammes daily, oral capsule

Intervention Type DRUG

Placebo oral capsule

4 grammes daily, oral capsule (olive oil)

Intervention Type DRUG

Other Intervention Names

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Lovaza Dummy

Eligibility Criteria

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Inclusion Criteria

1. Steatohepatitis diagnosed on normal clinical grounds including in most cases liver biopsy and assessed by Kleiner scoring system to assess severity, with no known aetiological factors for underlying liver disease (e.g. exclusion of hepatitis A, B \& C, primary biliary cirrhosis, autoimmune hepatitis, haemochromatosis).
2. Steatosis diagnosed by ultrasound, CT or magnetic resonance imaging who also have either diabetes and/or features of the metabolic syndrome, without evidence of known aetiological factors for underlying liver disease (e.g. exclusion of hepatitis A, B \& C, primary biliary cirrhosis, autoimmune hepatitis, haemochromatosis).

Liver biopsy or liver scan will be within 3 years of recruitment to the study. Age: men \& women \>18 years. Alcohol consumption \<35 units / week for women \<50 units / week for men).

Exclusion Criteria

* Decompensated acute or chronic liver disease, or harmful drinking (\> 35 u/week in women \> 50 u /week in men).
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Institute for Health Research, United Kingdom

OTHER_GOV

Sponsor Role collaborator

University Hospital Southampton NHS Foundation Trust

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Christopher D Byrne, MBBCh PhD

Role: PRINCIPAL_INVESTIGATOR

University of Southampton, UK

Locations

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Southamption General Hospital

Southampton, Hants, United Kingdom

Site Status

Countries

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United Kingdom

References

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Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Calder PC, Byrne CD; WELCOME Trial Investigators. Design and rationale of the WELCOME trial: A randomised, placebo controlled study to test the efficacy of purified long chainomega-3 fatty acid treatment in non-alcoholic fatty liver disease [corrected]. Contemp Clin Trials. 2014 Mar;37(2):301-11. doi: 10.1016/j.cct.2014.02.002. Epub 2014 Feb 18.

Reference Type BACKGROUND
PMID: 24556343 (View on PubMed)

Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, Kaye P, Burt AD, Ryder SD, Aithal GP, Day CP, Rosenberg WM. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008 Feb;47(2):455-60. doi: 10.1002/hep.21984.

Reference Type BACKGROUND
PMID: 18038452 (View on PubMed)

Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, Saksena S, Burt AD, Bida JP, Lindor K, Sanderson SO, Lenzi M, Adams LA, Kench J, Therneau TM, Day CP. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007 Apr;45(4):846-54. doi: 10.1002/hep.21496.

Reference Type BACKGROUND
PMID: 17393509 (View on PubMed)

Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Hodson L, Moyses HE, Calder PC, Byrne CD; WELCOME Study. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology. 2014 Oct;60(4):1211-21. doi: 10.1002/hep.27289.

Reference Type RESULT
PMID: 25043514 (View on PubMed)

Hodson L, Bhatia L, Scorletti E, Smith DE, Jackson NC, Shojaee-Moradie F, Umpleby M, Calder PC, Byrne CD. Docosahexaenoic acid enrichment in NAFLD is associated with improvements in hepatic metabolism and hepatic insulin sensitivity: a pilot study. Eur J Clin Nutr. 2017 Aug;71(8):973-979. doi: 10.1038/ejcn.2017.9. Epub 2017 Mar 15.

Reference Type DERIVED
PMID: 28294174 (View on PubMed)

Clough GF, McCormick KG, Scorletti E, Bhatia L, Calder PC, Griffin MJ, Byrne CD. Higher body fat percentage is associated with enhanced temperature perception in NAFLD: results from the randomised Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD with OMacor thErapy trial (WELCOME) trial. Diabetologia. 2016 Jul;59(7):1422-1429. doi: 10.1007/s00125-016-3966-8. Epub 2016 Apr 22.

Reference Type DERIVED
PMID: 27106721 (View on PubMed)

Bhatia L, Scorletti E, Curzen N, Clough GF, Calder PC, Byrne CD. Improvement in non-alcoholic fatty liver disease severity is associated with a reduction in carotid intima-media thickness progression. Atherosclerosis. 2016 Mar;246:13-20. doi: 10.1016/j.atherosclerosis.2015.12.028. Epub 2015 Dec 24.

Reference Type DERIVED
PMID: 26748347 (View on PubMed)

Byrne CD, Targher G. Time to Replace Assessment of Liver Histology With MR-Based Imaging Tests to Assess Efficacy of Interventions for Nonalcoholic Fatty Liver Disease. Gastroenterology. 2016 Jan;150(1):7-10. doi: 10.1053/j.gastro.2015.11.016. Epub 2015 Nov 18. No abstract available.

Reference Type DERIVED
PMID: 26602219 (View on PubMed)

Scorletti E, West AL, Bhatia L, Hoile SP, McCormick KG, Burdge GC, Lillycrop KA, Clough GF, Calder PC, Byrne CD. Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial. J Hepatol. 2015 Dec;63(6):1476-83. doi: 10.1016/j.jhep.2015.07.036. Epub 2015 Aug 10.

Reference Type DERIVED
PMID: 26272871 (View on PubMed)

McCormick KG, Scorletti E, Bhatia L, Calder PC, Griffin MJ, Clough GF, Byrne CD. Impact of high dose n-3 polyunsaturated fatty acid treatment on measures of microvascular function and vibration perception in non-alcoholic fatty liver disease: results from the randomised WELCOME trial. Diabetologia. 2015 Aug;58(8):1916-25. doi: 10.1007/s00125-015-3628-2. Epub 2015 May 29.

Reference Type DERIVED
PMID: 26021488 (View on PubMed)

Byrne CD, Targher G. Ectopic fat, insulin resistance, and nonalcoholic fatty liver disease: implications for cardiovascular disease. Arterioscler Thromb Vasc Biol. 2014 Jun;34(6):1155-61. doi: 10.1161/ATVBAHA.114.303034. Epub 2014 Apr 17.

Reference Type DERIVED
PMID: 24743428 (View on PubMed)

Targher G, Byrne CD. Clinical Review: Nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications. J Clin Endocrinol Metab. 2013 Feb;98(2):483-95. doi: 10.1210/jc.2012-3093. Epub 2013 Jan 4.

Reference Type DERIVED
PMID: 23293330 (View on PubMed)

Other Identifiers

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08/H0502/165

Identifier Type: OTHER

Identifier Source: secondary_id

25-12-59. (R&D: RHM MED 0836)

Identifier Type: -

Identifier Source: org_study_id

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