Clinical trial NCT04475276: Effect of Alpha Lipoic Acid on Non-alcoholic Fatty Liver Diseases
Official title: Effect of Alpha Lipoic Acid on Non-alcoholic Fatty Liver Diseases: A Randomized Placebo-controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Non-Alcoholic Fatty Liver Disease
Keywords: Non alcoholic fatty liver
Alphalipoic acid
Nutraceutic
Insulin resistance
Cytokeratin 18
Life style modification
Vitamin E
Lead sponsor: All India Institute of Medical Sciences, Bhubaneswar
Sponsor class: OTHER
First posted: 2020-07-17
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized, parallel design placebo-controlled clinical trial
Primary purpose: TREATMENT

Brief summary: In developed counties Non-alcoholic fatty liver disease (NAFLD) becomes the most common cause of chronic liver disease , but its prevalence in developing countries like India is also increasing (10 -20%).Till date, there is no US-FDA approved therapy for NAFLD but drugs like metformin, pioglitazone, sitagliptin, vildagliptin Vitamin E, silymarin, statins and ezetimibe have been studied along with life style modification. Life style modifications is the current modality of treatment of NAFLD. All the above-mentioned drugs have some beneficial effects with limited use due to its adverse effects in patients of NAFLD and the study results are non-conclusive. In this scenario, a safe hepatoprotective drug to be evaluated in NAFLD.Alpha-lipoic acid (ALA) or 6,8-thioctic acid, is an endogenous molecule which functions as an important co-factor for various enzyme complexes in mitochondria and plays an important role in energy metabolism. ALA is a nutraceutical agent which also has hepatoprotective and anti-inﬂammatory effects.ALA is a nutraceutic having anti-inflammatory and antioxidant effects and also increasing insulin sensitivity with lesser adverse effects. The relative scarcity of a promising therapy and non-conclusiveness of the previous studies open up an arena of further research using a nutraceutic in non-diabetic NAFLD. So, the present study is designed to evaluate safety and efficacy of ALA in non-diabetic NAFLD patients.

Detailed description: In developed counties Non-alcoholic fatty liver disease (NAFLD) becomes the most common cause of chronic liver disease , but its prevalence in developing countries like India is also increasing (10 -20%). Most of the patients are diagnosed clinically and by increased serum transaminase and fatty changes in liver on abdominal ultrasound. Till date, there is no US-FDA approved therapy for NAFLD but drugs like metformin, pioglitazone, sitagliptin, vildagliptin Vitamin E, silymarin, statins and ezetimibe have been studied along with life style modification. Life style modifications is the current modality of treatment of NAFLD. All the above-mentioned drugs have some beneficial effects with limited use due to its adverse effects in patients of NAFLD and the study results are non-conclusive. In this scenario, a safe hepatoprotective drug to be evaluated in NAFLD.

Alpha-lipoic acid (ALA) or 6,8-thioctic acid, is an endogenous molecule which functions as an important co-factor for various enzyme complexes in mitochondria and plays an important role in energy metabolism. ALA is a nutraceutical agent which also has hepatoprotective and anti-inﬂammatory effects. Previous animal studies proved the hepatoprotective effect of alpha lipoic acid on various animal models. Inflammatory liver injury involves the production of inflammatory mediators like nitric oxide and TNF-alpha. Alpha -Lipoic acid significantly inhibits production of nitric oxide and TNF-alpha. The reduced production of nitric oxide and TNF-alpha in Kupffer cells may be involved in the hepatoprotective action conveyed by alpha-lipoic acid.It has been proved that ALA has potent anti - inflammatory and anti- oxidant properties.

Insulin resistance is associated with impaired hepatic cell damage, intrahepatic cholestasis, atherogenic dyslipidaemia and fibrosis in patients of NAFLD. Daily treatment with ALA for 28 days significantly improved insulin sensitivity performance in mice by decreasing insulin resistance, IL-6 levels, acetylcholinesterase enzyme activity and oxidative stress in liver. Various studies have shown that the ALA can efficiently improve insulin sensitivity and reverse the insulin resistance. Cytokeratin 18 (CK 18) is released into circulation as a consequence of oxidative stress, hepatocyte apoptosis or inflammation in response to lipid metabolism in NAFLD. CK - 18 level is higher in insulin resistance.

ALA is a nutraceutic having anti-inflammatory and antioxidant effects and also increasing insulin sensitivity with lesser adverse effects. The relative scarcity of a promising therapy and non-conclusiveness of the previous studies open up an arena of further research using a nutraceutic in non-diabetic NAFLD. So, the present study is designed to evaluate safety and efficacy of ALA in non-diabetic NAFLD patients.

Eligibility criteria: Inclusion Criteria:

* All patients diagnosed to have fatty liver grading 1, 2, 3 on abdominal ultrasound, mild to moderate elevation (\<5 times elevated upper limit) of serum aminotransferase level.
* Patients aged 18-65 years of either sex.
* Treatment naïve patients or patients who had not taken any treatment for at least 4 weeks before inclusion

Exclusion Criteria:

* History of diabetes mellitus, decompensated liver disease, ascites, oesophageal varices.
* Drug abusers and Alcoholics.
* HBs Ag positive, Anti HCV and HIV, hereditary defects of iron, copper and alpha- 1 antitrypsin deficient patients.
* Hypothyroidism, obstructive sleep apnoea, total parenteral nutrition, short bowel syndrome, pancreatoduodenal resection which are secondary causes of NAFLD.
* Drug users such as corticosteroids, antiviral (nucleoside analogue), tetracycline, methotrexate, tamoxifen and amiodarone.
* Patients who are taking any antihyperlipidemic and anti-diabetic agents.

Primary outcomes:
measure: Abdominal ultrasound
timeFrame: 12 weeks
Secondary outcomes:
measure: Insulin resistance
timeFrame: 12 weeks
measure: Lipid profile
timeFrame: 12 weeks
measure: Levels of glutathione reductase
timeFrame: 12 weeks
measure: levels of Cytokeratin-18
timeFrame: 12 weeks
measure: Levels of Alanine transaminase (ALT)
timeFrame: 12 weeks
measure: Levels of Aspartate transaminase (AST)
timeFrame: 12 weeks
measure: Levels of Alkaline phosphatase (ALP)
timeFrame: 12 weeks
measure: Levels of Albumin and total protein.
timeFrame: 12 weeks
measure: Levels of Bilirubin
timeFrame: 12 weeks
measure: Levels of total protein
timeFrame: 12 weeks
measure: Levels of Gamma-glutamyltransferase (GGT).
timeFrame: 12 weeks
measure: Levels of L-lactate dehydrogenase (LDH).
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Bhubaneswar
country: India
facility: AIIMS
state: Odisha
Study officials:
affiliation: Additional Professor
name: Rituparna Maiti, MD
role: STUDY_DIRECTOR
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