Tocotrienol Against the Progression of End Stage Liver Disease

NCT02581085 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 1807361301136352
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this Phase 2 trial is to validate the outcome observed in a previous trial that oral Tocotrienol (TCT) attenuates the rise in MELD score over time in patients with end stage liver disease / cirrhosis. The study is double blind and participants will be randomized to take 2 capsules of TCT (200mg) or placebo twice a day for 3 years.

Conditions

End Stage Liver Disease; NASH - Nonalcoholic Steatohepatitis; NAFLD - Nonalcoholic Fatty Liver Disease

Keywords

Tocotrienol; Vitamin E

Outcome Measures

Primary Outcomes (1)

• Effect of Oral tocotrienols (TCT) on Model for End-Stage Liver Disease (MELD) score.

  Lab tests to calculate MELD score will be taken at baseline study visit and the last study visit ( Study visit 17 - 3 years) to see if Oral TCT will significantly attenuate the rise in MELD score over time in patients with End Stage Liver Disease / Cirrhosis

  3 years

Secondary Outcomes (11)

• Key Secondary Outcome

  3 yrs

• Change in Child-Pugh Score

  3 years

• Change in ALT Alanine transaminase

  3 years

• Events of hepatic decompensation

  3 yrs

• New onset ascites requiring treatment with or without paracentesis

  3 yrs

Study Arms (2)

Placebo Vehicle

PLACEBO COMPARATOR

Subjects will take 2 placebo capsules following AM meal, 2 placebo capsules following PM capsules

Other: Placebo

Tocotrienol supplement

ACTIVE COMPARATOR

Subjects will take (2) 200 mg TCT capsules following AM meal, (2) 200 mg TCT following PM meal

Drug: Tocotrienol (TCT)

Interventions

Tocotrienol (TCT) DRUG

TCT is a natural vitamin E supplement with a long history of safe dietary consumption in humans. The objective of the current trial is to validate the outcome observed in an earlier trial that oral TCT attenuates the rise in MELD score over time in patients with end stage liver disease/cirrhosis.

Tocotrienol supplement

Placebo OTHER

Control study capsule that includes no study product (Vitamin E - Tocotrienol)

Also known as: vehicle

Placebo Vehicle

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years of above, male or female
• ESLD patients with clinically- diagnosed NAFLD or NASH
• Absence of any other possible cause for liver dysfunction
• Stable MELD score of at least 8, but no greater than 17 with \<25% change in MELD over the past 60 days prior to enrollment (\*Total number of patients with MELD of 8-9 or MELD of 16-17 cannot exceed 40% of cohort)
• Able to speak and understand English
• Willing and able to provide informed consent
• Willing and able to return for regularly scheduled research study visits \& comply with study requirements

You may not qualify if:

• Rapid deterioration of liver function, as defined by an increase in MELD score ≥25% over the past 60 days prior to enrollment
• Hepatocellular carcinoma
• Positive HIV/AIDS, or other chronic immunodeficiency
• Concurrent hepatitis B or C infection
• Current drug and/or alcohol abuse (per treating physician)
• Bacterial infection at time of enrollment
• Daily use of dedicated vitamin E supplementation (greater than 100 IU per day) within the 3 months prior to study participation
• Platelets \<35,000 cells/µL, neutrophils \<1000 cells/µL, hemoglobin \<10g/dL, total bilirubin \>3mg/dL, serum creatinine \>2.0mg/dL
• Women who are pregnant, breastfeeding, or plan to become pregnant during course of study participation (36 months)
• Other significant comorbidities which limit the subject's life expectancy to less than 36 months
• Concurrent enrollment in another interventional clinical trial
• ALT \>250 U/L
• AST \> 250 U/L
• Hemoglobin A1C ≥ 9.5 %
• History of liver transplantation

Sponsors & Collaborators

• Chandan Sen: lead
• Malaysia Palm Oil Board: collaborator
• Indiana University: collaborator

Study Sites (1)

IU Health Unviersity Hospital

Indianapolis, Indiana, 46202, United States

Location

Related Publications (18)

• Patel V, Rink C, Gordillo GM, Khanna S, Gnyawali U, Roy S, Shneker B, Ganesh K, Phillips G, More JL, Sarkar A, Kirkpatrick R, Elkhammas EA, Klatte E, Miller M, Firstenberg MS, Chiocca EA, Nesaretnam K, Sen CK. Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients. J Nutr. 2012 Mar;142(3):513-9. doi: 10.3945/jn.111.151902. Epub 2012 Feb 1.

  PMID: 22298568 BACKGROUND

• Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, Karim R, Lin R, Samarasinghe D, Liddle C, Weltman M, George J. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002 Feb;35(2):373-9. doi: 10.1053/jhep.2002.30692.

  PMID: 11826411 BACKGROUND

• Ray K. NAFLD-the next global epidemic. Nat Rev Gastroenterol Hepatol. 2013 Nov;10(11):621. doi: 10.1038/nrgastro.2013.197. No abstract available.

  PMID: 24185985 BACKGROUND

• Schwenger KJ, Allard JP. Clinical approaches to non-alcoholic fatty liver disease. World J Gastroenterol. 2014 Feb 21;20(7):1712-23. doi: 10.3748/wjg.v20.i7.1712.

  PMID: 24587650 BACKGROUND

• Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ, Lavine JE. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005 Sep;42(3):641-9. doi: 10.1002/hep.20842.

  PMID: 16116629 BACKGROUND

• Review Team; LaBrecque DR, Abbas Z, Anania F, Ferenci P, Khan AG, Goh KL, Hamid SS, Isakov V, Lizarzabal M, Penaranda MM, Ramos JF, Sarin S, Stimac D, Thomson AB, Umar M, Krabshuis J, LeMair A; World Gastroenterology Organisation. World Gastroenterology Organisation global guidelines: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Clin Gastroenterol. 2014 Jul;48(6):467-73. doi: 10.1097/MCG.0000000000000116. No abstract available.

  PMID: 24921212 BACKGROUND

• Khanna S, Patel V, Rink C, Roy S, Sen CK. Delivery of orally supplemented alpha-tocotrienol to vital organs of rats and tocopherol-transport protein deficient mice. Free Radic Biol Med. 2005 Nov 15;39(10):1310-9. doi: 10.1016/j.freeradbiomed.2005.06.013.

  PMID: 16257640 BACKGROUND

• Khanna S, Rink C, Ghoorkhanian R, Gnyawali S, Heigel M, Wijesinghe DS, Chalfant CE, Chan YC, Banerjee J, Huang Y, Roy S, Sen CK. Loss of miR-29b following acute ischemic stroke contributes to neural cell death and infarct size. J Cereb Blood Flow Metab. 2013 Aug;33(8):1197-206. doi: 10.1038/jcbfm.2013.68. Epub 2013 May 1.

  PMID: 23632968 BACKGROUND

• Khanna S, Roy S, Slivka A, Craft TK, Chaki S, Rink C, Notestine MA, DeVries AC, Parinandi NL, Sen CK. Neuroprotective properties of the natural vitamin E alpha-tocotrienol. Stroke. 2005 Oct;36(10):2258-64. doi: 10.1161/01.STR.0000181082.70763.22. Epub 2005 Sep 15.

  PMID: 16166580 BACKGROUND

• Park HA, Kubicki N, Gnyawali S, Chan YC, Roy S, Khanna S, Sen CK. Natural vitamin E alpha-tocotrienol protects against ischemic stroke by induction of multidrug resistance-associated protein 1. Stroke. 2011 Aug;42(8):2308-14. doi: 10.1161/STROKEAHA.110.608547. Epub 2011 Jun 30.

  PMID: 21719775 BACKGROUND

• Patel V, Khanna S, Roy S, Ezziddin O, Sen CK. Natural vitamin E alpha-tocotrienol: retention in vital organs in response to long-term oral supplementation and withdrawal. Free Radic Res. 2006 Jul;40(7):763-71. doi: 10.1080/10715760600672491.

  PMID: 16984003 BACKGROUND

• Rink C, Christoforidis G, Khanna S, Peterson L, Patel Y, Khanna S, Abduljalil A, Irfanoglu O, Machiraju R, Bergdall VK, Sen CK. Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis. J Cereb Blood Flow Metab. 2011 Nov;31(11):2218-30. doi: 10.1038/jcbfm.2011.85. Epub 2011 Jun 15.

  PMID: 21673716 BACKGROUND

• Gopalan Y, Shuaib IL, Magosso E, Ansari MA, Abu Bakar MR, Wong JW, Khan NA, Liong WC, Sundram K, Ng BH, Karuthan C, Yuen KH. Clinical investigation of the protective effects of palm vitamin E tocotrienols on brain white matter. Stroke. 2014 May;45(5):1422-8. doi: 10.1161/STROKEAHA.113.004449. Epub 2014 Apr 3.

  PMID: 24699052 BACKGROUND

• Khosla P, Patel V, Whinter JM, Khanna S, Rakhkovskaya M, Roy S, Sen CK. Postprandial levels of the natural vitamin E tocotrienol in human circulation. Antioxid Redox Signal. 2006 May-Jun;8(5-6):1059-68. doi: 10.1089/ars.2006.8.1059.

  PMID: 16771695 BACKGROUND

• Mahipal A, Klapman J, Vignesh S, Yang CS, Neuger A, Chen DT, Malafa MP. Pharmacokinetics and safety of vitamin E delta-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites. Cancer Chemother Pharmacol. 2016 Jul;78(1):157-65. doi: 10.1007/s00280-016-3048-0. Epub 2016 Jun 8.

  PMID: 27278668 BACKGROUND

• Mangialasche F, Solomon A, Kareholt I, Hooshmand B, Cecchetti R, Fratiglioni L, Soininen H, Laatikainen T, Mecocci P, Kivipelto M. Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults. Exp Gerontol. 2013 Dec;48(12):1428-35. doi: 10.1016/j.exger.2013.09.006. Epub 2013 Oct 7.

  PMID: 24113154 BACKGROUND

• Meganathan P, Jabir RS, Fuang HG, Bhoo-Pathy N, Choudhury RB, Taib NA, Nesaretnam K, Chik Z. A new formulation of Gamma Delta Tocotrienol has superior bioavailability compared to existing Tocotrienol-Rich Fraction in healthy human subjects. Sci Rep. 2015 Sep 1;5:13550. doi: 10.1038/srep13550.

  PMID: 26323969 BACKGROUND

• Springett GM, Husain K, Neuger A, Centeno B, Chen DT, Hutchinson TZ, Lush RM, Sebti S, Malafa MP. A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E delta-tocotrienol in Patients with Pancreatic Ductal Neoplasia. EBioMedicine. 2015 Nov 14;2(12):1987-95. doi: 10.1016/j.ebiom.2015.11.025. eCollection 2015 Dec.

  PMID: 26844278 BACKGROUND

MeSH Terms

Conditions

End Stage Liver Disease; Non-alcoholic Fatty Liver Disease

Interventions

Tocotrienols

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Fatty Liver

Intervention Hierarchy (Ancestors)

Vitamin E; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Chandan K Sen, Ph.D

  University of Pittsburgh

  STUDY CHAIR

• Raj Vuppalanchi, M.D.

  Indiana Unviersity School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 26, 2015
• First Posted: October 20, 2015
• Study Start: November 1, 2019
• Primary Completion (Estimated): December 16, 2026
• Study Completion (Estimated): December 31, 2028
• Last Updated: February 9, 2026

Record last verified: 2026-01

Locations

US (1)