Clinical trial NCT02581085: Tocotrienol Against the Progression of End Stage Liver Disease
Official title: Tocotrienol Against the Progression of End Stage Liver Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: End Stage Liver Disease
NASH - Nonalcoholic Steatohepatitis
NAFLD - Nonalcoholic Fatty Liver Disease
Keywords: Tocotrienol
Vitamin E
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Malaysia Palm Oil Board
name: Indiana University
First posted: 2015-10-20
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Effect of Oral tocotrienols (TCT) on Model for End-Stage Liver Disease (MELD) score.
timeFrame: 3 years
Secondary outcomes:
measure: Change in Child-Pugh Score
timeFrame: 3 years
measure: Change in ALT Alanine transaminase
timeFrame: 3 years
measure: Events of hepatic decompensation
timeFrame: 3 yrs
measure: New onset ascites requiring treatment with or without paracentesis
timeFrame: 3 yrs
measure: GI bleed attributed to variceal bleeding
timeFrame: 3 yrs
measure: Hepatic encephalopathy requiring treatment
timeFrame: 3 yrs
measure: Need for Liver transplant
timeFrame: 3 yrs
measure: Death
timeFrame: 3 yrs
measure: Liver fibrosis
timeFrame: 3 yrs
measure: Adverse events
timeFrame: 3 yrs
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: IU Health Unviersity Hospital
state: Indiana
Study officials:
affiliation: University of Pittsburgh
name: Chandan K Sen, Ph.D
role: STUDY_CHAIR
affiliation: Indiana Unviersity School of Medicine
name: Raj Vuppalanchi, M.D.
role: PRINCIPAL_INVESTIGATOR
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