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

Study Overview
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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.

Official Title
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The Effects of Purified n-3 Fatty Acids on Serum Fibrosis Markers and Cardiovascular Risk Markers in a Randomized Placebo Controlled Trial in Patients With Non Alcoholic Fatty Liver Disease

Conditions
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Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: OMACOR
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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). 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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Omega 3 fatty acid (fish oil)<br>OMACOR (alternative name: Lovaza) 4 grammes daily, oral capsule | Drug: OMACOR<br>* 4 grammes daily, oral capsule<br>* Other names: Lovaza;|
| Placebo Comparator: dummy pill<br>4 grammes daily, oral capsule (olive oil) | Drug: Placebo oral capsule<br>* 4 grammes daily, oral capsule (olive oil)<br>* Other names: Dummy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Liver Fat | Percentage of liver fat was measured using magnetic resonance spectroscopy at baseline and end of study. High percentage values indicate a lot of liver fat (scale from 0 to 100%). Change in liver fat percentage represented the arithmetical difference between end of study liver fat percentage minus baseline measurement of liver fat percentage change in liver fat percentage was used to test whether the intervention decreased liver fat percentage. A negative change value in liver fat percentage indicates a response to therapy. A positive change value indicates no response to therapy. | Baseline and 18 months | 
| Liver Fibrosis Score | The Liver Fibrosis Score is an algorithmically derived score of liver fibrosis comprising measurements of tissue matrix metalloproteinase-1 (TIMP-1), hyaluronic acid (HA) and the amino terminal end of procollagen III (PIIINP) (see Guha et al. in Reference section). The Score represents a number on a numerical scale from 0 to 20. High values of the score (measured in arbitrary units) indicate high probability of advanced liver fibrosis, low scores indicate low probability of advanced liver fibrosis. Change in Liver Fibrosis Score was used to test the intervention. Change in liver fibrosis score represented the change in measurement as calculated as the arithmetic difference between the end value minus the baseline value of the Liver Fibrosis Score. The change in Liver Fibrosis Score can therefore be negative (representing an improvement in liver fibrosis between baseline and end of study) or be positive, (representing a worsening a liver fibrosis between baseline and end of study. | Baseline and 18 months | 
| NAFLD Fibrosis Score | The NAFLD fibrosis score represented a validated algorithmically-derived measure of liver fibrosis as reported in Angulo et al (see reference section). The Score is derived from anthropometric and biochemical measurements in subjects. The NAFLD fibrosis score represents an arbitrary number with no units from -5.0 to +5.0. High positive NAFLD fibrosis scores indicate a high probability of advanced liver fibrosis. Negative scores represent a low probability of advanced liver fibrosis. The change in NAFLD fibrosis score (measured in arbitrary units) was used to test the effect of the intervention and represented the arithmetic difference in the end minus baseline measurements of this score. Thus, a negative change in the Score in the Table represented an improvement in liver fibrosis score between baseline and the end of the study. A positive change in the Score in the Table represented a worsening in liver fibrosis score between baseline and end of the study. | Baseline and 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non alcoholic fatty liver disease, NAFLD, fish oil, intervention, RCT, biomarkers