The purpose of this Phase IIA trial is to validate the outcome observed in the Phase I trial that oral TCT attenuates the rise in MELD over time in patients diagnosed with NAFLD, NASH or chronically infected hepatitis C. Subjects will participate for 3 years. They will be asked to come to 8 total study visits and will receive 6 follow-up phone calls within the 3 years of participation. Subjects will be asked to take 2 study capsules of vitamin E Tocotrienol (200mg) twice a day or 2 placebo capsules twice a day. The study is randomized and study staff will be blinded to randomization.
Full Title of Study: “Tocotrienol Against the Progression of End Stage Liver Disease”
- Study Type: Observational
- Study Design
- Time Perspective: Prospective
- Study Primary Completion Date: February 2022
As a safe and natural vitamin, tocotrienol (TCT) stands uniquely poised to treat ~500 million worldwide who suffer from viral hepatitis. Furthermore, for those awaiting liver transplantation, TCT may buy more time until a liver becomes available. The primary purpose of this Phase IIA trial is to validate the outcome observed in the limited sample size Phase I trial (n=6) that oral TCT attenuates the rise in MELD over time in patients with NAFLD, NASH, or Hepatitis C. Outcomes will direct the design of a multi-center Phase IIB trial.
Study participation will last 3 years. Subjects will be seen for an initial visit, at which consent will be obtained and baseline labs drawn, followed by a Randomization visit 2-14 days later after MELD criteria have been confirmed. If the acceptable labs have not been drawn per standard of care to calculate a MELD score within 90 days before the initial visit, the subject will complete the initial visit as planned, but will then return for a repeat lab draw 60 days later to confirm MELD criteria for eligibility before continuing to the randomization visit.
Enrollment occurs when a subject meets all criteria and is randomized into one of the treatment groups. Subjects will then be seen in the research office by research personnel at 1 month, 2 months, 3 months, 6 months, 1 year, 18 months, 2 years, and 3 years. Subjects will receive follow-up phone calls at 9 months, 15 months, 21 months, 27 months, 30 months, and 33 months. Subject compliance with supplements will be closely followed, as compliance is critical for accurate data. Given the small sample size, subjects who are less than 75% compliant at two consecutive study visits will be discontinued from the study. Subjects will be discontinued if their MELD score increases by more than 25% between 2 consecutive visits or if they receive an organ transplant. Subjects will be declared lost to follow-up (LTFU) if a study visit is unable to be scheduled and completed after 4 documented attempts to contact a subject with no response. In this circumstance, a certified letter will be mailed to the subject's last known address; if no response is received, the subject is LTFU. All subjects discontinued or LTFU before the end of 1 year of study participation will be replaced (see protocol to review study visit activities that will occur). At the Randomization Visit, enrolled subjects will be randomized into one of two treatment groups in a 1:1 manner. Group 1: Placebo vehicle; (2) placebo capsules following AM meal, (2) placebo capsules following PM meal Group 2: 800mg TCT; (2) 200mg TCT capsules following AM meal, (2) 200mg TCT capsules following PM meal
- Drug: Tocotrienol
- Vitamin E is a dietary supplement. Vitamin E is a fat-soluble vitamin that exists in eight different forms. Each form has its own biological activity, which is the measure of potency or functional use in the body. Vitamin E is a dietary antioxidant that assists in maintaining cell integrity. It is obtained from sunflower, safflower, canola, and olive oils; also from many grains, nuts, fruits as well as fatty parts of meats. The tocotrienol form of natural vitamin E is found in rice and cereals but more abundantly in palm oil. Palm oil is an integral part of daily diet in southeastern Asia
- Other: Placebo
- Control study capsule that includes no study product (Vitamin E – Tocotrienol)
Arms, Groups and Cohorts
- Placebo Vehicle
- Subjects will take 2 placebo capsules following AM meal, 2 placebo capsules following PM capsules
- Tocotrienol supplement
- Subjects will take (2) 200 mg TCT capsules following AM meal, (2) 200 mg TCT following PM meal
Clinical Trial Outcome Measures
- Effect of Oral tocotrienols (TCT) on Model for End-Stage Liver Disease (MELD) score
- Time Frame: 3 years
- Lab tests including viral load viral, viral genotype, bilirubmin, fibrosure, and INR will be taken at baseline study visit and the last study visit ( Study visit 8 – 3 years) and will calculate MELD scores to see if Oral TCT will significantly attenuate the rise in MELD score over time in patients with End Stage Liver Disease
Participating in This Clinical Trial
- Age 18 years of above, male or female
- ESLD patients with clinically- diagnosed NAFLD, NASH, or chronically infected with hepatitis C virus (HCV, all genotypes), with amount of virus in the blood greater than 10,000 IU/ml
- Absence of any other possible cause for liver dysfunction
- Stable MELD score of at least 8, but no greater than 15 over the past 6 months (+/- 1 month) prior to enrollment
- 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
- Rapid deterioration of liver function, over the past 6 months (+/- 1 month) prior to enrollment per study physician determination
- Hepatocellular carcinoma
- Positive HIV/ AIDS, or other chronic immunodeficiency
- Concurrent hepatitis A or B infection
- Current drug and/or alcohol abuse (per treating physician)
- Bacterial infection at time of enrollment
- Daily use of dedicated vitamin E supplementation within the 12 months prior to study participation
- Platelets <25,000 cells/µL, neutrophils <1000 cells/µL, hemoglobin <8g/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
- Patients receiving medications known to treat Hepatitis C; patients who begin taking these medications during the course of study participation will be dropped.
Gender Eligibility: All
Minimum Age: 18 Years
Maximum Age: N/A
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- Indiana University
- Malaysia Palm Oil Board
- Provider of Information About this Clinical Study
- Principal Investigator: Chandan Sen, Professor – Indiana University
- Overall Official(s)
- Chandan K Sen, Ph.D, Principal Investigator, The Ohio State University Wexner Medical Center
- Overall Contact(s)
- Jennifer Mohnacky, RN, 317-278-2715, email@example.com
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.
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.
Ray K. NAFLD-the next global epidemic. Nat Rev Gastroenterol Hepatol. 2013 Nov;10(11):621. doi: 10.1038/nrgastro.2013.197.
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. Review.
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.
Review Team, LaBrecque DR, Abbas Z, Anania F, Ferenci P, Khan AG, Goh KL, Hamid SS, Isakov V, Lizarzabal M, Peñaranda 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.
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.
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.
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. Epub 2005 Sep 15.
Park HA, Kubicki N, Gnyawali S, Chan YC, Roy S, Khanna S, Sen CK. Natural vitamin E α-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.
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.
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.
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.
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.
Mahipal A, Klapman J, Vignesh S, Yang CS, Neuger A, Chen DT, Malafa MP. Pharmacokinetics and safety of vitamin E δ-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.
Mangialasche F, Solomon A, Kåreholt 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.
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.
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 δ-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.
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