Role of Obeticholic Acid in the Patients of NAFLD With Raised ALT
Condition: Non-Alcoholic Fatty Liver Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional

Summary: 
      This study will be conducted upon the patients with fatty liver disease. Patients who will be
      diagnosed as a case of fatty liver disease by ultrasound with raised liver enzyme (ALT) will
      be primarily selected for the study. A total number of 70 patients will be randomly selected
      for the study that will also be divided into two groups for the study purpose. The patients
      will be informed about the details of the study. After getting the detail information those
      who will give informed written consent will be finally included in the study. One group of
      patients will be treated by both life style modification and Obeticholic acid. Another group
      of patients by only life style modification. After 3 months of treatment the two groups will
      be compared of improvement of fatty liver disease and liver enzyme by improvement of
      fibroscan with CAP value as well as improvement of ALT value.
    

Detailed description: 
      Non-alcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver
      disease worldwide and it is associated with increased liver-related mortality and
      hepatocellular carcinoma, even in the absence of cirrhosis. The prevalence of NAFLD is
      steadily increasing and is currently 20%-30% in Western countries and 5%-18% in Asia. It
      progresses to cirrhosis in 15-20% of affected individuals and is a rising indication for
      liver transplantation. NAFLD is the commonest cause of elevated liver enzymes. Lifestyle
      modifications, including diet and exercise, are imperative for achieving weight loss and
      reducing insulin resistance and hepatic steatosis and inflammation in patients with NAFLD.
      But are suboptimal by long-term adherence in patients with NAFLD. On the other hand, current
      pharmacological treatment of NAFLD has limited efficacy and unfavorable safety profile. In
      this context, obeticholic acid, a selective agonist of the farnesoid X receptors, might
      represent a useful option in these patients. Preclinical studies suggest that obeticholic
      acid improves hepatic steatosis, inflammation and fibrosis. A randomized, placebo-controlled
      Farnesoid X Receptor Ligand Obeticholic Acid in non-alcoholic steatohepatitis Treatment
      (FLINT) trial also showed improvements in liver histology in patients with NAFLD who received
      obeticholic acid. So, there is a need to develop more effective and safe agents for this
      common and life-threatening disease.

      Farnesoid X receptor (FXR) is a member of the nuclear receptor super family expressed in the
      liver, kidney, intestine and adrenal glands. In addition to regulation of bile acid (BA)
      synthesis, several lines of evidence have suggested that FXR plays a role in the
      pathophysiology of NAFLD/NASH. Obeticholic acid is a synthetically modified bile acid that is
      a potent agonist of the farnesoid X nuclear receptor (FXR), a nuclear receptor with major
      effects on bile acid synthesis and transport as well as lipid metabolism and glucose
      homeostasis. Obeticholic acid has been shown to improve serum enzymes in several diseases
      including nonalcoholic fatty liver disease and primary biliary cirrhosis. In FLINT trial
      treatment with obeticholic acid (25 mg/day for 72 weeks) resulted in a highly statistically
      significant improvement in the NAFLD Activity Score of at least two points, with no worsening
      of fibrosis. 45% (50 of 110) of the treated group had this improvement compared with 21% (23
      of 109) of the placebo-treated controls.

      The objective of the study will be to assess the efficacy of obeticholic acid on improvement
      of NAFLD and ALT values in patients with fatty liver disease.

      The study will be conducted in the department of Hepatology, Sir Salimullah Medical College
      and Mitford Hospital. It will be a randomized open label clinical control trial study.
      Patients diagnosed with non-alcoholic fatty liver disease (NAFLD) will be initially targeted
      for the study. Patients who will be diagnosed as a case of NAFLD by ultrasound with raised
      Alanin aminotransferase (ALT) (>40 U/L) will be primarily selected for the study. The total
      sample size will be 70 that will be divided into two groups (Group-A and Group-B) for the
      study purpose. The patients will be informed about the details of the study. After getting
      the detail information, those who will give informed written consent will be finally included
      in the study. A series of baseline investigations including CBC with ESR, fasting blood sugar
      (FBS), 2 hours after 75 g glucose, alanine aminotransferase (ALT), aspartate-aminotransferase
      (AST), gamma-glutamyl transpeptidase (GGT), bilirubin (B), PT with INR, serum albumin, total
      cholesterol (TC) & triglycerides (TG), LDL-C, HDL-C, Thyroid function test will be determined
      on fresh serum using an auto-analyzer. Fibroscan with CAP as well as ALT will be done to
      assess the baseline status of the patients at the time of enrollment of the study. Group-A
      patients will be treated by both life style modification and Obeticholic acid and Group-B
      patients by only life style modification. We shall give 10 mg obeticholic acid twice daily to
      the patients of Group-1. Life style modification including moderate exercise that is 30
      minutes brisk walking a day with dietary advice to avoid fatty foods and excessive sugar
      containing diet and intake of at least 3 vegetables per day will be advised to all the
      patients in both Groups. The patients will be followed for 3 months. Patients will come for
      follow-up after 1 month and finally after 3 months. Each visit will take place between 10.00
      am to 02.00 p.m. & consist with a clinical examination, blood pressure (BP) & body mass index
      (BMI) determinations and a questionnaire. BMI will be computed using the formula: [weight
      (kg)]/ [square of height (meters)]. Serum will be collected for CBC with ESR, FBS, 2 hours
      after 75 g glucose, ALT, AST, PT with INR, serum albumin, GGT, TC, TG, HDL, LDL in first and
      last visit. An alcohol consumption questionnaire will also be administered in each visit and
      study compliance will be strictly monitored. After 3 months of treatment the two groups will
      be compared of improvement of NAFLD and liver enzyme by improvement of fibroscan with CAP
      value as well as improvement of ALT value with the baseline ALT and fibroscan with CAP
      values.

      All Data will be presented as mean ± SD & analyzed by SPSS (version 23). Qualitative data
      will be analyzed by Chi-square test & quantitative data will be analyzed by student's t-test.
      A statistically significant result will be considered when P value < 0.05.
    

Intervention name(s): Obeticholic acid
Intervention type(s): Drug
Intervention description(s): Farnesoid X receptor ligand which is a semi synthetic bile acid analogue
Other intervention name(s): Life style modification
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Open label randomized clinical control trial study
Masking: None (Open Label)
Primary purpose: Treatment