Tocotrienol Against the Progression of End Stage Liver Disease

NASH - Nonalcoholic Steatohepatitis Clinical Trial

Official title:

Tocotrienol Against the Progression of End Stage Liver Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02581085
• Other study ID #: 1807361301
• Status: Recruiting
• Phase: Phase 2
• Start date: November 1, 2019
• Est. completion date: December 31, 2028

Study information

• Verified date: July 2023
• Source: Indiana University
• Contact: Kaitlyn Depinet, FNP-C
• Phone: 3172782747
• Email: kdepinet[@]iu.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Tocotrienol (TCT) is a natural vitamin E supplement with a long history of safe dietary consumption. Prior studies with Vitamin E have shown beneficial effects in patients with non-alcoholic fatty liver disease and cirrhosis. The primary purpose of this Phase 2 trial is to validate the outcome observed in an earlier trial that oral TCT attenuates the rise in MELD (Model For End-Stage Liver Disease) score over time in patients with cirrhosis. Outcomes of this trail will direct the design of a future larger multi-center 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 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 18 months, 2 years, and 3 years. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: December 31, 2028
• Est. primary completion date: December 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

1. Rapid deterioration of liver function, as defined by an increase in MELD score =25% over the past 60 days prior to enrollment

2. Hepatocellular carcinoma

3. Positive HIV/AIDS, or other chronic immunodeficiency

4. Concurrent hepatitis B or C infection

5. Current drug and/or alcohol abuse (per treating physician)

6. Bacterial infection at time of enrollment

7. Daily use of dedicated vitamin E supplementation (greater than 100 IU per day) within the 3 months prior to study participation

8. Platelets <35,000 cells/µL, neutrophils <1000 cells/µL, hemoglobin <10g/dL, total bilirubin >3mg/dL, serum creatinine >2.0mg/dL

9. Women who are pregnant, breastfeeding, or plan to become pregnant during course of study participation (36 months)

10. Other significant comorbidities which limit the subject's life expectancy to less than 36 months

11. Concurrent enrollment in another interventional clinical trial

12. ALT >250 U/L

13. AST > 250 U/L

14. Hemoglobin A1C = 9.5 %

15. History of liver transplantation

16. Current or history of HCC

17. Any weight reduction surgery in the preceding 2 years prior to screening or planned surgery during the study

18. Malignancy within 5 years of screening with the exception of a Adequately treated carcinoma in situ of the cervix b. Adequately treated basal or squamous cell cancer or other localized non-melanoma skin cancer

Related Conditions & MeSH terms

• End Stage Liver Disease
• Fatty Liver
• Liver Diseases
• NAFLD - Nonalcoholic Fatty Liver Disease
• NASH - Nonalcoholic Steatohepatitis
• Non-alcoholic Fatty Liver Disease

Intervention

Drug:
• Tocotrienol (TCT)
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.

Other:
• Placebo
Control study capsule that includes no study product (Vitamin E - Tocotrienol)

Locations

Country	Name	City	State
United States	IU Health Unviersity Hospital	Indianapolis	Indiana

Sponsors (2)

Lead Sponsor	Collaborator
Indiana University	Malaysia Palm Oil Board

Country where clinical trial is conducted

United States, 

References & Publications (18)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Change in Child-Pugh Score	change in Child-Pugh Score	3 years
Secondary	Change in ALT Alanine transaminase	Change in ALT (Alanine transaminase)	3 years
Secondary	Events of hepatic decompensation	Events of hepatic decompensation	3 yrs
Secondary	New onset ascites requiring treatment with or without paracentesis	New onset ascites requiring treatment with or without paracentesis	3 yrs
Secondary	GI bleed attributed to variceal bleeding	GI bleed attributed to variceal bleeding, requires evaluation by an endoscopy	3 yrs
Secondary	Hepatic encephalopathy requiring treatment	Hepatic encephalopathy requiring treatment, Grade 2 or above according to West Haven Criteria	3 yrs
Secondary	Need for Liver transplant	Need for liver transplant	3 yrs
Secondary	Death	did death occur	3 yrs
Secondary	Liver fibrosis	Liver fibrosis as measured by change in LSM by vibration-controlled transient elastography	3 yrs
Secondary	Adverse events	Did any AEs occur	3 yrs