Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis
Conditions
Keywords
Vitamin E, Nonalcoholic Fatty Liver Disease
Brief summary
This is a multicenter, randomized, double masked, placebo-controlled, parallel treatment groups dosing trial of Vitamin E in adult nonalcoholic fatty liver disease (NAFLD).
Detailed description
Adults age 18 years or older will be enrolled for 48 weeks and treated with 200 international units (IU), 400 IU, or 800 IU of Vitamin E or matching placebo for 24 weeks. The primary objective of the study is to determine the minimum effective dose of Vitamin E (d-alpha-tocopherol) based upon relative change in alanine aminotransferase (ALT) from baseline to 24 weeks.
Interventions
DRUGVitamin E
Participants will be assigned to take 200 IU, 400 IU, or 800 IU of vitamin E in matching capsules daily for 24 weeks
DRUGPlacebo
Participants will take a placebo vitamin E capsule daily for 24 weeks
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Duke University
Liver Institute Northwest
Indiana University
St. Louis University
University of California, San Diego
University of Southern California
University of California, San Francisco
Virginia Commonwealth University
The Cleveland Clinic
Johns Hopkins Bloomberg School of Public Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
multicenter, randomized, double masked, placebo-controlled, parallel treatment groups
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years of age or older as of the initial screening interview and provision of consent * FibroScan CAP\>280 dB/m within 60 days prior to randomization. * ALT ≥ 60 U/L within 30 days of randomization
Exclusion criteria
* Concurrent or prior use (within 90 days) of vitamin E supplements in excess of 40 IU/day * Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 g/day (\~1.5 drinks/day) (\> 10.5 drinks per week) in females and more than 30 g/day (\~2 drinks/day) (\>14 drinks per week) in males, respectively. One "standard" drink (or one alcoholic drink equivalent) contains roughly 14 grams of pure alcohol, which is found in: 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces of distilled spirits). * Inability to reliably quantify alcohol consumption based upon local study physician judgment * Continued use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) for more than 2 weeks in the 6 months prior to randomization * Current use of anticoagulation therapy (not including antiplatelet agents such as aspirin or clopidogrel) * Platelet count below 150,000 /mm3 within 90 days of randomization * History of condition(s) that cause increased risk of bleeding, including hemophilia A, hemophilia B, von Willebrand disease, or other clotting factor deficiencies. * Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y gastric bypass) * Uncontrolled diabetes defined as HbA1c 9.5% or higher within 60 days prior to randomization * Clinical evidence of hepatic decompensation as defined by the presence of any of the following abnormalities: * Serum albumin less than 3.2 g/dL * International Normalized Ratio (INR) greater than 1.3 * Direct bilirubin greater than 1.0 mg/dL * History of esophageal varices, ascites or hepatic encephalopathy * Evidence of other forms of chronic liver disease: * Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg) * Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA * Evidence of ongoing autoimmune liver disease as defined by compatible liver histology * Primary biliary cirrhosis as defined by the presence of at least 2 of these criteria (i) Biochemical evidence of cholestasis based mainly on alkaline phosphatase elevation (ii) Presence of anti-mitochondrial antibody (AMA) (iii) Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts\[1\] * Primary sclerosing cholangitis * Known history of Wilson disease, alpha-1-antitrypsin liver disease, or hemochromatosis. Any other type of liver disease that is currently active other than NASH such as drug-induced liver disease, liver cancer, or bile duct obstruction. * Serum alanine aminotransferase (ALT) greater than 400 U/L within 90 days of randomization * Moderate or severe renal impairment (serum creatinine ≥ 2.0 mg/dL or eGFR \< 60 mg/mL/1.73m2) * History of biliary diversion or evidence of current biliary obstruction * Known positivity for Human Immunodeficiency Virus (HIV) infection * Active, serious medical disease with likely life expectancy less than 5 years * Active substance abuse including inhaled or injection drugs in the year prior to screening * Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use ≥ 1 effective form(s) of birth control during the trial, breast feeding * Current use of medications that may impact the absorption of fat-soluble vitamins (i.e. orlistat or cholestyramine) * Pre-existing history of fat malabsorption * Males at high risk of prostate cancer, including: * PSA \>ULN at baseline * History of prostate cancer * Age 45 or older with a first-degree relative (father or brother) diagnosed with prostate cancer at an early age (younger than age 65). * Age 40 or older with more than one first-degree relative who had prostate cancer at an early age (younger than age 65) * Participation in an IND trial in the 30 days before randomization * Any other condition which, in the opinion of the investigator, would impede compliance or hinder completion of the study, including inability to swallow treatment capsules * Failure or inability to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change in Alanine Aminotransferase (ALT) From Baseline to 24 Weeks | Baseline to 24 weeks (end of treatment) | Percent change from baseline to 24 weeks relative to baseline measure of ALT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Achieving Normalization of Alanine Aminotransferase (ALT) at 24 Weeks | Baseline to 24 weeks (end of treatment) | Normalization of ALT (U/L) is defined as a decrease in ALT to less than or equal to the ULN at the 24 week visit among participants who had an ALT value greater than ULN at baseline. Values for upper limits of normal (ULN) are defined at each clinical center per institutional guidelines. |
| Mean Change in Serum Alanine Aminotransferase (ALT) From Baseline | Baseline to 24 weeks (end of treatment) | ALT value in U/L |
| Mean Change in Serum Aspartate Aminotransferase (AST) From Baseline | Baseline to 24 weeks (end of treatment) | AST value in U/L |
| Mean Change in Hepatic Steatosis (Fat in the Liver) Determined by Fibroscan® Controlled Attenuation Parameter (CAP) Software Function | Baseline to24 weeks (end of treatment) | CAP (Control Attenuation Parameter) is expressed in decibels per meter (dB/m). This value is the median of all valid measurements performed during the examination. It ranges from 100 to 400 dB/m. Higher dB/m indicates worse liver fat. |
| Mean Change in Liver Stiffness From Baseline Assessed by Fibroscan® | Baseline to 24 weeks (end of treatment) | Fibroscan® measures stiffness in kiloPascal's (kPa) and ranges from 2 to 75. Normal range of FibroScan is between 2 to 7 kPa, and the average normal result is 5.3kPa. Higher kPa means more stiffness (scarring). |
| Mean Change in Gamma-glutamyl Transferase (GGT) From Baseline to 24 Weeks | Baseline to 24 weeks (end of treatment) | GGT is measured in U/L |
| Mean Change in Glucose From Baseline to 24 Weeks | Baseline to 24 weeks (end of treatment) | Fasting glucose measured in mg/dL |
| Mean Change in Weight From Baseline to 24 Weeks | Baseline to 24 weeks (end of treatment) | Weight measured in kilograms (kg) |
| Mean Change in Body Mass Index (BMI) From Baseline to 24 Weeks | Baseline to 24 weeks (end of treatment) | BMI is reported in kg/m-squared |
| Mean Change in Waist Circumference From Baseline to 24 Weeks | Baseline to 24 weeks (end of treatment) | Waist circumference measured in centimeters (cm) |
| Mean Change in Waist-to-hip Ratio From Baseline to 24 Weeks | Baseline to 24 weeks (end of treatment) | Waist-to-hip ratio from baseline to 24 weeks |
| Mean Change in Liver Symptom Questionnaire Total Score | Baseline to 24 weeks (end of treatment) | The Liver Symptom Questionnaire scores 10 symptoms of liver disease on a scale of 1-5. Higher scores mean higher symptom severity. Total score can range from 10-50. |
| Mean Change in ALT From 24 to 48 Weeks | 24 weeks (end of treatment) to 48 weeks (final study visit) | Change in ALT (U/L) during off treatment phase |
| Mean Change in AST From 24 to 48 Weeks | 24 weeks (end of treatment) to 48 weeks (final study visit) | AST value in U/L |
| Mean Change in GGT From 24 to 48 Weeks | 24 weeks (end of treatment) to 48 weeks (final study visit) | GGT is measured in U/L |
| Mean Change in Controlled Attenuation Parameter (CAP) From 24 to 48 Weeks | 24 weeks (end of treatment) to 48 weeks (final study visit) | CAP (Control Attenuation Parameter) is expressed in decibels per meter (dB/m). This value is the median of all valid measurements performed during the examination. It ranges from 100 to 400 dB/m. Higher dB/m indicates worse liver fat. |
| Mean Change in Liver Stiffness Measure (LSM) From 24 to 48 Weeks | 24 weeks (end of treatment) to 48 weeks (final study visit) | LSM is measured in kPa |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORArun Sanyal, MD
Virginia Commonwealth University
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 48.2 years STANDARD_DEVIATION 14.1 |
| Alanine Aminotransferase (ALT) | 94 U/L |
| Aspartate Aminotransferase (AST) | 56 U/L |
| Controlled Attenuation Parameter (CAP) score | 320 dB/m |
| Ethnicity (NIH/OMB) Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 165 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Liver stiffness | 8 kPa |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants |
| Race (NIH/OMB) White | 150 Participants |
| Region of Enrollment United States | 48 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 51 | 0 / 51 | 0 / 48 |
| other Total, other adverse events | 9 / 50 | 10 / 51 | 11 / 51 | 11 / 48 |
| serious Total, serious adverse events | 3 / 50 | 2 / 51 | 2 / 51 | 1 / 48 |
Outcome results
None listed