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Tocotrienol Against the Progression of End Stage Liver Disease

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ClinicalTrials.gov Identifier: NCT02581085
Recruitment Status : Recruiting
First Posted : October 20, 2015
Last Update Posted : February 8, 2023
Malaysia Palm Oil Board
Information provided by (Responsible Party):
Raj Vuppalanchi, Indiana University

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.

Condition or disease Intervention/treatment Phase
End Stage Liver Disease NASH - Nonalcoholic Steatohepatitis NAFLD - Nonalcoholic Fatty Liver Disease Drug: Tocotrienol (TCT) Other: Placebo Phase 2

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Other
Official Title: Tocotrienol Against the Progression of End Stage Liver Disease
Actual Study Start Date : November 1, 2019
Estimated Primary Completion Date : December 31, 2027
Estimated Study Completion Date : December 31, 2028

Arm Intervention/treatment
Placebo Comparator: Placebo Vehicle
Subjects will take 2 placebo capsules following AM meal, 2 placebo capsules following PM capsules
Other: Placebo
Control study capsule that includes no study product (Vitamin E - Tocotrienol)
Other Name: vehicle

Active Comparator: Tocotrienol supplement
Subjects will take (2) 200 mg TCT capsules following AM meal, (2) 200 mg TCT following PM meal
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.

Primary Outcome Measures :
  1. Effect of Oral tocotrienols (TCT) on Model for End-Stage Liver Disease (MELD) score. [ Time Frame: 3 years ]
    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

Secondary Outcome Measures :
  1. Change in Child-Pugh Score [ Time Frame: 3 years ]
    change in Child-Pugh Score

  2. Change in ALT Alanine transaminase [ Time Frame: 3 years ]
    Change in ALT (Alanine transaminase)

  3. Events of hepatic decompensation [ Time Frame: 3 yrs ]
    Events of hepatic decompensation

  4. New onset ascites requiring treatment with or without paracentesis [ Time Frame: 3 yrs ]
    New onset ascites requiring treatment with or without paracentesis

  5. GI bleed attributed to variceal bleeding [ Time Frame: 3 yrs ]
    GI bleed attributed to variceal bleeding, requires evaluation by an endoscopy

  6. Hepatic encephalopathy requiring treatment [ Time Frame: 3 yrs ]
    Hepatic encephalopathy requiring treatment, Grade 2 or above according to West Haven Criteria

  7. Need for Liver transplant [ Time Frame: 3 yrs ]
    Need for liver transplant

  8. Death [ Time Frame: 3 yrs ]
    did death occur

  9. Liver fibrosis [ Time Frame: 3 yrs ]
    Liver fibrosis as measured by change in LSM by vibration-controlled transient elastography

  10. Adverse events [ Time Frame: 3 yrs ]
    Did any AEs occur

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02581085

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Contact: Amy Miller 317-278-2720 amym@iu.edu
Contact: Sashwati Roy, Ph.D 3172782706 roysa@iu.edu

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United States, Indiana
IU Health Unviersity Hospital Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Heather Adams, RN    317-962-1130    hejadams@iu.edu   
Contact: Anna Smith, RN       asmith81@iuhealth.org   
Sponsors and Collaborators
Indiana University
Malaysia Palm Oil Board
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Study Chair: Chandan K Sen, Ph.D Indiana University School of Medicine
Principal Investigator: Raj Vuppalanchi, M.D. Indiana Unviersity School of Medicine

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Responsible Party: Raj Vuppalanchi, Professor, Indiana University
ClinicalTrials.gov Identifier: NCT02581085    
Other Study ID Numbers: 1807361301
First Posted: October 20, 2015    Key Record Dates
Last Update Posted: February 8, 2023
Last Verified: February 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Raj Vuppalanchi, Indiana University:
Vitamin E
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
End Stage Liver Disease
Digestive System Diseases
Liver Failure
Hepatic Insufficiency
Vitamin E
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs