Effect of Alpha Lipoic Acid on Non-alcoholic Fatty Liver Diseases

Non-Alcoholic Fatty Liver Disease Clinical Trial

Official title:

Effect of Alpha Lipoic Acid on Non-alcoholic Fatty Liver Diseases: A Randomized Placebo-controlled Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04475276
• Other study ID #: T/IM-F/19-20/16
• Status: Recruiting
• Phase: Phase 4
• Start date: February 23, 2021
• Est. completion date: December 31, 2023

Study information

• Verified date: December 2023
• Source: All India Institute of Medical Sciences, Bhubaneswar
• Contact: Monalisa Jena, MD
• Phone: 9438884193
• Email: drmonalisajena[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-Alcoholic Fatty Liver Disease

Intervention

Drug:
• Placebo
Lifestyle modification with placebo for 12 weeks
• Alphalipoic acid
Lifestyle modification with Alphalipoic acid for 12 weeks

Locations

Country	Name	City	State
India	AIIMS	Bhubaneswar	Odisha

Sponsors (1)

Lead Sponsor	Collaborator
All India Institute of Medical Sciences, Bhubaneswar

Country where clinical trial is conducted

India, 

References & Publications (14)

Abdel-Daim MM, Taha R, Ghazy EW, El-Sayed YS. Synergistic ameliorative effects of sesame oil and alpha-lipoic acid against subacute diazinon toxicity in rats: hematological, biochemical, and antioxidant studies. Can J Physiol Pharmacol. 2016 Jan;94(1):81- — View Citation

Ahuja S, Uniyal A, Akhtar A, Sah SP. Alpha lipoic acid and metformin alleviates experimentally induced insulin resistance and cognitive deficit by modulation of TLR2 signalling. Pharmacol Rep. 2019 Aug;71(4):614-623. doi: 10.1016/j.pharep.2019.02.016. Epu — View Citation

Cavestro C, Bedogni G, Molinari F, Mandrino S, Rota E, Frigeri MC. Alpha-Lipoic Acid Shows Promise to Improve Migraine in Patients with Insulin Resistance: A 6-Month Exploratory Study. J Med Food. 2018 Mar;21(3):269-273. doi: 10.1089/jmf.2017.0068. Epub 2 — View Citation

Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, Sebastiani G, Ekstedt M, Hagstrom H, Nasr P, Stal P, Wong VW, Kechagias S, Hultcrantz R, Loomba R. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic rev — View Citation

Fayez AM, Zakaria S, Moustafa D. Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats. Biomed Pharmacother. 2018 Sep;105:428-433. doi: 10.1016/j.bioph — View Citation

He L, Deng L, Zhang Q, Guo J, Zhou J, Song W, Yuan F. Diagnostic Value of CK-18, FGF-21, and Related Biomarker Panel in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Biomed Res Int. 2017;2017:9729107. doi: 10.1155/2017/9729107. — View Citation

Hussain M, Majeed Babar MZ, Hussain MS, Akhtar L. Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with non alcoholic fatty liver disease. Pak J Med Sci. 2016 Nov-Dec;32(6):1396-1401. doi: 10.12669/pjms.326.11133. — View Citation

Khalaf AA, Zaki AR, Galal MK, Ogaly HA, Ibrahim MA, Hassan A. The potential protective effect of alpha-lipoic acid against nanocopper particle-induced hepatotoxicity in male rats. Hum Exp Toxicol. 2017 Sep;36(9):881-891. doi: 10.1177/0960327116674526. Epu — View Citation

Patel SS, Siddiqui MS. Current and Emerging Therapies for Non-alcoholic Fatty Liver Disease. Drugs. 2019 Jan;79(1):75-84. doi: 10.1007/s40265-018-1040-1. — View Citation

Sadek KM, Saleh EA, Nasr SM. Molecular hepatoprotective effects of lipoic acid against carbon tetrachloride-induced liver fibrosis in rats: Hepatoprotection at molecular level. Hum Exp Toxicol. 2018 Feb;37(2):142-154. doi: 10.1177/0960327117693066. Epub 2 — View Citation

Schurks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010 Nov 4;341:c5702. doi: 10.1136/bmj.c5702. — View Citation

Singh SP, Misra B, Kar SK, Panigrahi MK, Misra D, Bhuyan P, Pattnaik K, Meher C, Agrawal O, Rout N, Swain M. Nonalcoholic fatty liver disease (NAFLD) without insulin resistance: Is it different? Clin Res Hepatol Gastroenterol. 2015 Sep;39(4):482-8. doi: 1 — View Citation

Tomic D, Kemp WW, Roberts SK. Nonalcoholic fatty liver disease: current concepts, epidemiology and management strategies. Eur J Gastroenterol Hepatol. 2018 Oct;30(10):1103-1115. doi: 10.1097/MEG.0000000000001235. — View Citation

Wu G, Li H, Fang Q, Zhang J, Zhang M, Zhang L, Wu L, Hou X, Lu J, Bao Y, Jia W. Complementary Role of Fibroblast Growth Factor 21 and Cytokeratin 18 in Monitoring the Different Stages of Nonalcoholic Fatty Liver Disease. Sci Rep. 2017 Jul 11;7(1):5095. do — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Abdominal ultrasound	the change in fatty liver grading in NAFLD assessed by abdominal ultrasound	12 weeks
Secondary	Insulin resistance	changes in insulin resistance by using HOMA IR after therapy	12 weeks
Secondary	Lipid profile	Change in lipid profile (Total Cholesterol, HDL, LDL,Triglycerides, VLDL) after therapy; •	12 weeks
Secondary	Levels of glutathione reductase	changes in levels of glutathione reductase after therapy	12 weeks
Secondary	levels of Cytokeratin-18	changes in levels of Cytokeratin-18 after therapy	12 weeks
Secondary	Levels of Alanine transaminase (ALT)	changes in Alanine transaminase units per litre after therapy	12 weeks
Secondary	Levels of Aspartate transaminase (AST)	changes in Aspartate transaminase (AST)units per litre after therapy	12 weeks
Secondary	Levels of Alkaline phosphatase (ALP)	changes in Alkaline phosphatase (ALP) in IU after therapy	12 weeks
Secondary	Levels of Albumin and total protein.	changes in Albumin and total protein in gm/L after therapy	12 weeks
Secondary	Levels of Bilirubin	changes in Bilirubin in µmol/L after therapy	12 weeks
Secondary	Levels of total protein	changes in total protein in gm/L after therapy	12 weeks
Secondary	Levels of Gamma-glutamyltransferase (GGT).	changes in Gamma-glutamyltransferase (GGT) units per liter after therapy	12 weeks
Secondary	Levels of L-lactate dehydrogenase (LDH).	changes in L-lactate dehydrogenase (LDH) units per liter after therapy	12 weeks