Non-Alcoholic Fatty Liver DiseasePhase 2PUVENAFLDNCT04198805
Vitamin E and DHA-EE on NAFLD - Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Clinical Trial (PUVENAFLD)
A Phase 2 study testing Vitamin E [(all-rac)-α-tocopheryl acetate], Omega-3 fatty acid (DHA EE) and Omega-3 fatty acid (DHA EE) & Vitamin E [(all-rac)-α-tocopheryl acetate] in people with Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Fatty Liver, run by Naga P. Chalasani at 15 sites in United States.
Trial summary
Multicenter, randomized, double-blinded, placebo-controlled clinical trial is focused on novel treatments for non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Fatty Liver, Non-Alcoholic Steatohepatitis
- What is being tested?
- Vitamin E [(all-rac)-α-tocopheryl acetate], Omega-3 fatty acid (DHA EE) and Omega-3 fatty acid (DHA EE) & Vitamin E [(all-rac)-α-tocopheryl acetate]
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 205 participants
- Where
- 15 sitesUnited States
- Study dates
- 3 Jan 2020to 1 Sep 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female gender
- ≥18 years of age
- A new diagnosis or reconfirmation of previously known fatty liver by imaging (ultrasound or CT or MRI), or by liver biopsy within ≤ 4 years
- Fibroscan CAP score >300db
- Hepatic fat fraction ≥12% by MRI PDFF
- ALT≥ 40 U/L
Show all 10Show fewer
- eGFR/Creatinine Clearance ≥ 60ml/min
- Participants with previously diagnosed Type 2 diabetes (up to 50% of sample): they must either be taking anti-diabetic medications, or their fasting (>10 hours) glucose must be ≥ 100 mg/dL at the time of screening
- Stable weight (±5%) for at least 3 months
- Subjects willing and able to give written informed consent and to understand, to participant and to comply with the clinical study requirements.
Who cannot join
- Evidence of alternative causes of hepatic steatosis or other forms of chronic liver disease, e.g. Hep.B, Hep.C
- Evidence of acute Hepatitis A
- Serum ALT or AST ≥ 250 U/L
- Serum Alkaline Phosphatase > 2 ULN
- Total bilirubin > 2 ULN in the absence of Gilbert's Syndrome [In patients with Gilbert's Syndrome, direct bilirubin must not exceed 2 ULN]
- HbA1c≥9.5%
Show all 27Show fewer
- Decompensated acute or chronic liver disease
- Clinical, imaging or histological evidence of cirrhosis
- Use of anti-NASH drugs (e.g. thiazolidinediones) in the 3 months prior to randomization
- Use of a non-stable dose of statins or fibrates in the 3 months prior to randomization
- Use of fish oil, algal oil or Krill oil supplements, drugs or foods fortified with omega-3s in the 2 months prior to randomization (>200mg DHA/d and/or >60mg EPA/d by FFQ)
- Known intolerance to vitamin E or DHA
- Malabsorption of Vit E (e.g. due to steatorrhea, chronic pancreatitis, severe cholestasis)
- Vitamin E supplementation of greater than 100 IU/day in the 3 months prior to randomization
- History of bariatric surgery (jejunoileal bypass or gastric weight loss surgery) or currently undergoing evaluation for bariatric surgery
- History of biliary diversion
- Known positivity for antibody to Human Immunodeficiency Virus (HIV)
- Patients with coagulopathy (PT ≥3 sec.from ULN), thrombocytopenia (<70K)
- Contraindication to MRI (implants, metal…)
- Active, serious medical disease or disease diagnosis of a life-expectancy less than 5 years
- Ongoing or recent alcohol consumption > 21 drinks (1 drink= 12 oz regular beer, or 5 oz wine, or 1.5 oz distilled spirits) per week in men and > 14 drinks per week in women as per subject self-report as part of medical history.
- Active substance abuse, such as oral, inhaled or injected illicit drugs (except marijuana), in the year prior to screening
- Women of childbearing potential: positive pregnancy test during screening or at randomization or unwillingness to use an effective form of birth control during the trial
- Women who are breastfeeding
- Any other condition which, in the opinion of the investigator would impede compliance or hinder completion of the study
- Subjects who are enrolled in an interventional clinical study or have received an investigational new drug or product within the last 30 days prior to screening
- Participants diagnosed with type 1 diabetes
Trial locations and contacts
15 sites in 1 country.
15 sites in 1 country
United States15 sites
Summit Clinical Research LLC
Athens, Georgia, 30607
Arizona Liver Health
Chandler, Arizona, 85712
Integrity Clinical Research LLC
Doral, Florida, 33166
Indago Research and Health Center, Inc.
Hialeah, Florida, 33012
Centex Studies, Inc.
Houston, Texas, 77058
Liver Specialists of Texas/Mt. Olympus Medical Research
Houston, Texas, 77479
Indiana University School of Medicine
Indianapolis, Indiana, 46202
Florida Research Institute
Lakewood Rch, Florida, 34211
Advanced Pharma CR LLC
Miami, Florida, 33147
Med-Care Research
Miami, Florida, 33165
Arkansas Gastroenterology
North Little Rock, Arkansas, 72117
M3 Wake Research Associates
Raleigh, North Carolina, 27612
Inland Empire Clinical Trials, LLC
Rialto, California, 92377
American Research Corporation at the Texas Liver Institute
San Antonio, Texas, 78215
Arizona Liver Health
Tucson, Arizona, 85712
About this study
Official title: The Effect of Vitamin E and Docosahexaenoic Acid Ethyl Ester on Non-Alcoholic Fatty Liver Disease (NAFLD) - Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Clinical Trial (PUVENAFLD)
Multicenter, randomized, double-blinded, placebo-controlled clinical trial is focused on novel treatments for non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease. The primary objective of the study is to determine the clinical efficacy and safety of Vitamin E [(all-rac)-α-tocopheryl acetate] and Omega-3 fatty acid (DHA EE) compared to placebo on reducing liver fat content in participants with NAFLD. There is currently no approved drug treatment for NAFLD or NASH. While several new targets are being evaluated, they are not sufficiently powered to provide definitive data. There is, therefore, a need for well-designed, appropriately powered efficacy (phase 2) trials to define the utility of newer therapies for NAFLD. The combination of Vitamin E and DHA may provide optimal benefit for patients with NAFLD due to their associated mechanisms of action, namely Vitamin E's antioxidant action, preventing lipid oxidation of long-chain fatty acids such as DHA and thus preventing the propagation of free radicals and ROS.
Read the detailed description
Background information
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the liver and is defined by evidence of hepatic steatosis (via imaging or histology) and is not due to secondary liver fat accumulation from excessive alcohol consumption or hereditary disorders (e.g., Wilson's disease). NAFLD is most commonly associated with metabolic syndrome, consisting of obesity, insulin resistance, elevated blood pressure, and dyslipidemia. NAFLD is one of the most common causes of chronic liver disease, globally with a prevalence as high as 30% in Western countries. It includes a spectrum of diseases from steatosis to non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma. Non-alcoholic fatty liver does not involve hepatocellular injury in the form of ballooning hepatocytes, whereas NASH is defined by steatosis, inflammation, and hepatocyte injury (ballooning) with or without fibrosis. The causes of NAFLD are likely due to a combination of genetic and physiologic factors, namely those that promote oxidative stress and inflammation such as metabolic syndrome, visceral adiposity, and changes in intestinal microbiota. NAFLD is significantly associated with increased risk of Type II Diabetes and cardiovascular disease and increased overall mortality compared to age-matched controls. There is currently no approved drug treatment for NAFLD or NASH. Dietary restrictions for weight loss and increased physical activity are the recommended therapies, albeit with limited success.
Investigational products
Vitamin E [(all-rac)-α-tocopheryl acetate]
Vitamin E is a fat-soluble vitamin that is synthesized naturally in plants in four tocopheryl forms: α, β, γ, and δ. All-rac-α-tocopheryl acetate has the highest biological activity in animal models, and it is the α-tocopheryl form that is used to prevent and treat Vitamin E deficiency in humans. Functionally, Vitamin E is an anti-oxidant and peroxyl radical scavenger. It is an inhibitor of lipid peroxidation and can also inhibit and modulate intracellular signaling molecules, e.g., protein kinase C, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. α-tocopheryl regulates gene expression of several intracellular enzymes such as 5-lipoxygenase and cyclooxygenase and has anti-inflammatory activity (i.e., decreasing cytokine release and plasma C reactive protein). It is also known to inhibit platelet adhesion and aggregation. \
DHA Ethyl Ester
Long-chain polyunsaturated fatty acid (LC-PUFA), docosahexaenoic acid (DHA) is an essential omega-3 fatty acid for brain, eye and cardiovascular development and health. It significantly reduces triglycerides (TGs), lowers heart rate, lowers blood pressure, and reduces the risk of cardiac death by an overall 8%. Both DHA and eicosapentaenoic acid (EPA) have anti-thrombotic, anti-inflammatory, and anti-oxidative properties. As NAFLD patients are at significantly greater risk of cardiovascular disease and higher overall mortality, the cardioprotective effects of DHA are significant and may be beneficial in the NAFLD population.
Potential mechanisms for DHA's effects in NAFLD include the reduction of TG synthesis via activation of peroxisome proliferator-activated receptors (PPAR-α and γ), which accelerates fatty acid oxidation in liver mitochondria. DHA is also known to have an integral role in maintaining and improving cell membrane fluidity, as a fatty acid that is incorporated into the phospholipids of the membrane, thereby optimizing surface receptors and signal transduction pathways in liver cells. The anti-inflammatory role of DHA in NAFLD may be mediated through activation of adiponectin secretion through adults with NAFLD. MRI-PDFF is also an appropriate technique to diagnose and stage disease in those with metabolic syndrome and NAFLD. The clinical trial is designed to test the combination of Vitamin E and DHA against placebo, to demonstrate efficacy and safety.
Rationale for conducting the clinical study
The combination of Vitamin E and DHA has not been tested in previous clinical trials of adults with NAFLD. This combination may provide optimal benefit for patients with NAFLD due to their associated mechanisms of action, namely Vitamin E's antioxidant action, preventing lipid oxidation of long-chain fatty acids such as DHA and thus preventing the propagation of free radicals and ROS. Vitamin E's protection of LC-PUFA DHA, therefore, assists it in maintaining cell membrane stability and optimal signaling. Their combined anti-inflammatory effects (e.g., inhibiting pro-inflammatory cytokines, increasing adiponectin, and producing docosanoids to resolve inflammation) may also be efficacious for those with metabolic syndrome and NAFLD. The combination of Vitamin E and DHA will correctly be used in this study to determine if a reduction in liver fat occurs after six months of co-administration, using a magnetic resonance imaging (MRI) technique, proton density fat fraction (PDFF). PDFF imaging is non-invasive and highly sensitive to detect liver steatosis in patients with NAFLD.
- Conditions
- Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Fatty Liver, Non-Alcoholic Steatohepatitis
- Being tested
- Vitamin E [(all-rac)-α-tocopheryl acetate], Omega-3 fatty acid (DHA EE), Omega-3 fatty acid (DHA EE) & Vitamin E [(all-rac)-α-tocopheryl acetate], Placebo
- Keywords
- Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Fatty Liver, NAFL, NAFLD, Vitamin E, DHA
- Medical subject headings
- Non-alcoholic Fatty Liver Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Vitamin E [(all-rac)-α-tocopheryl acetate]Dietary supplement
Vitamin E (1000 mg) once daily for 6 months (1 capsule) and matching placebos (2 matched capsules) for 6 months
Omega-3 fatty acid (DHA EE)Dietary supplement
DHA EE (1.89 g) once daily for 6 months (2 capsules) and matching placebo for DHA EE (1 matched capsule for 6 months)
Omega-3 fatty acid (DHA EE) & Vitamin E [(all-rac)-α-tocopheryl acetate]Combination product
Also called Vitamin E [(all-rac)-α-tocopheryl acetate]
DHA EE (1.89 g) once daily for 6 months and Vitamin E (1000 mg) once daily for 6 months
PlaceboOther
Matching soybean placebo (3 capsules) of all arms daily for 6 months.
| Study group | Role | What they receive |
|---|---|---|
| Vitamin E (1000 mg) | Active comparator | Vitamin E (1000 mg) once daily for 6 months (1 capsule) and matching placebos (2 matched capsules) for 6 months. Receives: Dietary Supplement: Vitamin E [(all-rac)-α-tocopheryl acetate] |
| DHA EE (1.89 g) | Active comparator | DHA EE (1.89 g) once daily for 6 months (2 capsules) and matching placebo for DHA EE (1 matched capsule for 6 months). Receives: Dietary Supplement: Omega-3 fatty acid (DHA EE) |
| DHA EE (1.89 g) and Vitamin E (1000 mg) | Active comparator | DHA EE (1.89 g) once daily for 6 months and Vitamin E (1000 mg) once daily for 6 months. Receives: Combination Product: Omega-3 fatty acid (DHA EE) & Vitamin E [(all-rac)-α-tocopheryl acetate] |
| Placebo | Placebo comparator | Matching soybean oil placebo (3 capsules) of all arms daily for 6 months. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Hepatic Fat Fraction [%] Between of Vitamin E and DHA EE vs Placebo
A change in liver fat content relative to baseline between Vitamin E and DHA EE vs placebo. This will be measured by MRI-PDFF at baseline and after 6 months of intervention (value at 6 months minus value at baseline).
Measured: Baseline to 6 months
Secondary outcomes (23)
Change in Hepatic Fat Fraction [%] Between Vitamin E vs Placebo Arm
Change in liver fat content relative to baseline between Vitamin E vs placebo arm. This will be measured by MRI-PDFF at baseline and after 6 months of intervention (value at 6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Hepatic Fat Fraction [%] Between DHA EE vs Placebo Arm
Change in liver fat content relative to baseline between DHA EE vs placebo arm. This will be measured by MRI-PDFF at baseline and after 6 months of intervention (value at 6 months minus value at baseline).
Measured: Baseline to 6 months
Change After 6 Months of DHA EE and/ or Vitamin E Intervention in the Anthropometric Measure, Waist Circumference.
Evaluation of baseline and 6 month measurements of waist circumference in the DHA EE and /or Vitamin E intervention over a 6 month period.
Measured: Baseline to 6 months
Change After 6 Months of DHA EE and /or Vitamin E Intervention in the Anthropometric Measure, Bodyweight.
Evaluation of baseline and 6-month measurements of body weight in the DHA EE and /or Vitamin E intervention over a 6 month period.
Measured: Baseline to 6 months
Change After 6 Months of DHA EE and/ or Vitamin E Intervention in the Anthropometric Measure, Waist-to-hip Ratio .
Evaluation of baseline and 6-month measurements of waist-to-hip ratio (the circumference of the waist divided by the circumference of the hips) in the DHA EE and /or Vitamin E intervention over a 6 month period.
Measured: Baseline to 6 months
Change After 6 Months of DHA EE and/ or Vitamin E Intervention in the Anthropometric Measure, Body Mass Index (BMI)
Evaluation of baseline and 6-month measurements of body mass index (BMI) in the DHA EE and /or Vitamin E intervention over a 6 month period.
Measured: Baseline to 6 months
Change in Insulin Levels to Determine Insulin Resistance
Measured: Baseline to 6 months
Change in Liver Enzymes (ALT) in the DHA EE and /or Vitamin E Intervention Over a 6 Month Period.
Evaluation of baseline and 6-month liver enzymes: alanine transaminase (ALT) in the DHA EE and /or Vitamin E intervention over a 6 month period value at (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Liver Enzymes (AST) in the DHA EE and /or Vitamin E Intervention Over a 6 Month Period.
Evaluation of baseline and 6-month liver enzymes: aspartate aminotransferase (AST) in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Liver Enzymes Bilirubin in the DHA EE and /or Vitamin E Intervention Over a 6 Month Period.
Evaluation of baseline and 6-month liver enzymes: Bilirubin in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Liver Enzymes Alkaline Phosphatase in the DHA EE and /or Vitamin E Intervention Over a 6 Month Period.
Evaluation of baseline and 6-month liver enzymes: Alkaline Phosphatase in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Fibrosis-4 (FIB-4) Score
The formula for FIB-4 is: Age ([yr] x AST [U/L]) / ((PLT [10(9)/L]) x (ALT [U/L])(1/2)). A value of FIB-4 below 1.30 is considered as low risk for advanced fibrosis; a value of FIB-4 over 2.67 is considered as high risk for advanced fibrosis
Measured: Baseline to 6 months
Change in Plasma Vitamin E Concentration
Evaluation of baseline and 6-month plasma Vitamin E concentration in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Plasma DHA EE Concentration
Evaluation of baseline and 6-month plasma DHA EE concentration in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Lipid Profile (HDL-C)
Evaluation of baseline and 6-month lipid profile (HDL-C) in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Lipid Profile (Low Density Lipoprotein (LDL-C))
Evaluation of baseline and 6-month lipid profile (low density lipoprotein (LDL-C))in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Lipid Profile (Triglycerides)
Evaluation of baseline and 6-month lipid profile (TGs)in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Lipid Profile (Oxidized LDL)
Evaluation of baseline and 6-month lipid profile (oxidized LDL) in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Health Related Quality of Life Score (Short Form (SF-36))
Evaluation of baseline and 6-month quality of life score (SF-36) in the DHA EE and /or Vitamin E intervention over a 6 month period (value at 6 months minus value at baseline). The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability
Measured: Baseline to 6 months
Change in Dietary Intake Levels of Long-chain Polyunsaturated Fatty Acids (LC-PUFA ) (i.e. DHA and EPA) as Measured by the Food Frequency Questionnaire (FFQ)
Evaluation of baseline and 6-month dietary intake levels of LC-PUFA (i.e. DHA and EPA) as measured by the Food Frequency Questionnaire (FFQ)in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Inflammatory Markers (Cytokeratin 18 (CK-18))
Evaluation of baseline and 6-month inflammatory markers (cytokeratin 18) in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Inflammatory Markers (IL-1β)
Evaluation of baseline and 6-month inflammatory markers (IL-1β) in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Change in Inflammatory Markers (TNFα)
Evaluation of baseline and 6-month inflammatory markers (TNFα) in the DHA EE and /or Vitamin E intervention over a 6 month period (6 months minus value at baseline).
Measured: Baseline to 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Dec 2019
- Study start3 Jan 2020
- Primary completion1 Sep 2022
- Study completion1 Sep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Non-Alcoholic Fatty Liver DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 205 participants (actual)
Sponsor and investigators
- Lead sponsor
- Naga P. Chalasani
- Sponsor type
- University, hospital or other
- Collaborators
- dsm-firmenich Switzerland AG
- Responsible party
- Sponsor-investigator, Naga P. Chalasani, Indiana University
- Investigators
- Naga P. Chalasani, MD, Principal investigator, Indiana University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04198805
- Sponsor's protocol ID
- 2017-1088
- Acronym
- PUVENAFLD
- Status last verified
- Apr 2023
- First submitted
- 30 Oct 2019
- Last updated
- 25 May 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 25 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Vitamin E and Docosahexaenoic Acid Ethyl Ester on Non-Alcoholic Fatty Liver Disease (NAFLD) - Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Clinical Trial (PUVENAFLD)
- ClinicalTrials.gov ID
- NCT04198805
- Acronym / sponsor ID
- PUVENAFLD / 2017-1088
- Conditions
- Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Fatty Liver, Non-Alcoholic Steatohepatitis
- Keywords
- Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Fatty Liver, NAFL, NAFLD, Vitamin E, DHA
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 205 participants (actual)
- Lead sponsor
- Naga P. ChalasaniUniversity, hospital or other
- Collaborators
- dsm-firmenich Switzerland AG
- Study start
- 3 Jan 2020 (actual)
- Primary completion
- 1 Sep 2022 (actual)
- Study completion
- 1 Sep 2022 (actual)
- First posted
- 13 Dec 2019 (actual)
- Results
- Posted 25 May 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Multicenter, randomized, double-blinded, placebo-controlled clinical trial is focused on novel treatments for non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease. The primary objective of the study is to determine the clinical efficacy and safety of Vitamin E [(all-rac)-α-tocopheryl acetate] and Omega-3 fatty acid (DHA EE) compared to placebo on reducing liver fat content in participants with NAFLD. There is currently no approved drug treatment for NAFLD or NASH. While several new targets are being evaluated, they are not sufficiently powered to provide definitive data. There is, therefore, a need for well-designed, appropriately powered efficacy (phase 2) trials to define the utility of newer therapies for NAFLD. The combination of Vitamin E and DHA may provide optimal benefit for patients with NAFLD due to their associated mechanisms of action, namely Vitamin E's antioxidant action, preventing lipid oxidation of long-chain fatty acids such as DHA and thus preventing the propagation of free radicals and ROS.
Detailed description
Background information
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the liver and is defined by evidence of hepatic steatosis (via imaging or histology) and is not due to secondary liver fat accumulation from excessive alcohol consumption or hereditary disorders (e.g., Wilson's disease). NAFLD is most commonly associated with metabolic syndrome, consisting of obesity, insulin resistance, elevated blood pressure, and dyslipidemia. NAFLD is one of the most common causes of chronic liver disease, globally with a prevalence as high as 30% in Western countries. It includes a spectrum of diseases from steatosis to non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma. Non-alcoholic fatty liver does not involve hepatocellular injury in the form of ballooning hepatocytes, whereas NASH is defined by steatosis, inflammation, and hepatocyte injury (ballooning) with or without fibrosis. The causes of NAFLD are likely due to a combination of genetic and physiologic factors, namely those that promote oxidative stress and inflammation such as metabolic syndrome, visceral adiposity, and changes in intestinal microbiota. NAFLD is significantly associated with increased risk of Type II Diabetes and cardiovascular disease and increased overall mortality compared to age-matched controls. There is currently no approved drug treatment for NAFLD or NASH. Dietary restrictions for weight loss and increased physical activity are the recommended therapies, albeit with limited success.
Investigational products
Vitamin E [(all-rac)-α-tocopheryl acetate]
Vitamin E is a fat-soluble vitamin that is synthesized naturally in plants in four tocopheryl forms: α, β, γ, and δ. All-rac-α-tocopheryl acetate has the highest biological activity in animal models, and it is the α-tocopheryl form that is used to prevent and treat Vitamin E deficiency in humans. Functionally, Vitamin E is an anti-oxidant and peroxyl radical scavenger. It is an inhibitor of lipid peroxidation and can also inhibit and modulate intracellular signaling molecules, e.g., protein kinase C, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. α-tocopheryl regulates gene expression of several intracellular enzymes such as 5-lipoxygenase and cyclooxygenase and has anti-inflammatory activity (i.e., decreasing cytokine release and plasma C reactive protein). It is also known to inhibit platelet adhesion and aggregation. \
DHA Ethyl Ester
Long-chain polyunsaturated fatty acid (LC-PUFA), docosahexaenoic acid (DHA) is an essential omega-3 fatty acid for brain, eye and cardiovascular development and health. It significantly reduces triglycerides (TGs), lowers heart rate, lowers blood pressure, and reduces the risk of cardiac death by an overall 8%. Both DHA and eicosapentaenoic acid (EPA) have anti-thrombotic, anti-inflammatory, and anti-oxidative properties. As NAFLD patients are at significantly greater risk of cardiovascular disease and higher overall mortality, the cardioprotective effects of DHA are significant and may be beneficial in the NAFLD population.
Potential mechanisms for DHA's effects in NAFLD include the reduction of TG synthesis via activation of peroxisome proliferator-activated receptors (PPAR-α and γ), which accelerates fatty acid oxidation in liver mitochondria. DHA is also known to have an integral role in maintaining and improving cell membrane fluidity, as a fatty acid that is incorporated into the phospholipids of the membrane, thereby optimizing surface receptors and signal transduction pathways in liver cells. The anti-inflammatory role of DHA in NAFLD may be mediated through activation of adiponectin secretion through adults with NAFLD. MRI-PDFF is also an appropriate technique to diagnose and stage disease in those with metabolic syndrome and NAFLD. The clinical trial is designed to test the combination of Vitamin E and DHA against placebo, to demonstrate efficacy and safety.
Rationale for conducting the clinical study
The combination of Vitamin E and DHA has not been tested in previous clinical trials of adults with NAFLD. This combination may provide optimal benefit for patients with NAFLD due to their associated mechanisms of action, namely Vitamin E's antioxidant action, preventing lipid oxidation of long-chain fatty acids such as DHA and thus preventing the propagation of free radicals and ROS. Vitamin E's protection of LC-PUFA DHA, therefore, assists it in maintaining cell membrane stability and optimal signaling. Their combined anti-inflammatory effects (e.g., inhibiting pro-inflammatory cytokines, increasing adiponectin, and producing docosanoids to resolve inflammation) may also be efficacious for those with metabolic syndrome and NAFLD. The combination of Vitamin E and DHA will correctly be used in this study to determine if a reduction in liver fat occurs after six months of co-administration, using a magnetic resonance imaging (MRI) technique, proton density fat fraction (PDFF). PDFF imaging is non-invasive and highly sensitive to detect liver steatosis in patients with NAFLD.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Vitamin E (1000 mg) | Active comparator | Dietary Supplement: Vitamin E [(all-rac)-α-tocopheryl acetate]Vitamin E (1000 mg) once daily for 6 months (1 capsule) and matching placebos (2 matched capsules) for 6 months. |
| DHA EE (1.89 g) | Active comparator | Dietary Supplement: Omega-3 fatty acid (DHA EE)DHA EE (1.89 g) once daily for 6 months (2 capsules) and matching placebo for DHA EE (1 matched capsule for 6 months). |
| DHA EE (1.89 g) and Vitamin E (1000 mg) | Active comparator | Combination Product: Omega-3 fatty acid (DHA EE) & Vitamin E [(all-rac)-α-tocopheryl acetate]DHA EE (1.89 g) once daily for 6 months and Vitamin E (1000 mg) once daily for 6 months. |
| Placebo | Placebo comparator | Other: PlaceboMatching soybean oil placebo (3 capsules) of all arms daily for 6 months. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Male or female gender
- ≥18 years of age
- A new diagnosis or reconfirmation of previously known fatty liver by imaging (ultrasound or CT or MRI), or by liver biopsy within ≤ 4 years
- Fibroscan CAP score >300db
- Hepatic fat fraction ≥12% by MRI PDFF
Key exclusion criteria (27 listed)
- Evidence of alternative causes of hepatic steatosis or other forms of chronic liver disease, e.g. Hep.B, Hep.C
- Evidence of acute Hepatitis A
- Serum ALT or AST ≥ 250 U/L
- Serum Alkaline Phosphatase > 2 ULN
- Total bilirubin > 2 ULN in the absence of Gilbert's Syndrome [In patients with Gilbert's Syndrome, direct bilirubin must not exceed 2 ULN]
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Vitamin E [(all-rac)-α-tocopheryl acetate]Vitamin E (1000 mg) once daily for 6 months (1 capsule) and matching placebos (2 matched capsules) for 6 months | Dietary supplement | Vitamin E (1000 mg) |
| Omega-3 fatty acid (DHA EE)DHA EE (1.89 g) once daily for 6 months (2 capsules) and matching placebo for DHA EE (1 matched capsule for 6 months) | Dietary supplement | DHA EE (1.89 g) |
| Omega-3 fatty acid (DHA EE) & Vitamin E [(all-rac)-α-tocopheryl acetate]Also: Vitamin E [(all-rac)-α-tocopheryl acetate]DHA EE (1.89 g) once daily for 6 months and Vitamin E (1000 mg) once daily for 6 months | Combination product | DHA EE (1.89 g) and Vitamin E (1000 mg) |
| PlaceboMatching soybean placebo (3 capsules) of all arms daily for 6 months. | Other | Placebo |
Primary outcome
Change in Hepatic Fat Fraction [%] Between of Vitamin E and DHA EE vs Placebo
Time frame: Baseline to 6 months
A change in liver fat content relative to baseline between Vitamin E and DHA EE vs placebo. This will be measured by MRI-PDFF at baseline and after 6 months of intervention (value at 6 months minus value at baseline).
23 secondary outcomes
Change in Hepatic Fat Fraction [%] Between Vitamin E vs Placebo Arm
Time frame: Baseline to 6 months
Change in Hepatic Fat Fraction [%] Between DHA EE vs Placebo Arm
Time frame: Baseline to 6 months
Change After 6 Months of DHA EE and/ or Vitamin E Intervention in the Anthropometric Measure, Waist Circumference.
Time frame: Baseline to 6 months
Change After 6 Months of DHA EE and /or Vitamin E Intervention in the Anthropometric Measure, Bodyweight.
Time frame: Baseline to 6 months
Change After 6 Months of DHA EE and/ or Vitamin E Intervention in the Anthropometric Measure, Waist-to-hip Ratio .
Time frame: Baseline to 6 months
Change After 6 Months of DHA EE and/ or Vitamin E Intervention in the Anthropometric Measure, Body Mass Index (BMI)
Time frame: Baseline to 6 months
Change in Insulin Levels to Determine Insulin Resistance
Time frame: Baseline to 6 months
Change in Liver Enzymes (ALT) in the DHA EE and /or Vitamin E Intervention Over a 6 Month Period.
Time frame: Baseline to 6 months
Change in Liver Enzymes (AST) in the DHA EE and /or Vitamin E Intervention Over a 6 Month Period.
Time frame: Baseline to 6 months
Change in Liver Enzymes Bilirubin in the DHA EE and /or Vitamin E Intervention Over a 6 Month Period.
Time frame: Baseline to 6 months
Liver Enzymes Alkaline Phosphatase in the DHA EE and /or Vitamin E Intervention Over a 6 Month Period.
Time frame: Baseline to 6 months
Change in Fibrosis-4 (FIB-4) Score
Time frame: Baseline to 6 months
Change in Plasma Vitamin E Concentration
Time frame: Baseline to 6 months
Change in Plasma DHA EE Concentration
Time frame: Baseline to 6 months
Change in Lipid Profile (HDL-C)
Time frame: Baseline to 6 months
Change in Lipid Profile (Low Density Lipoprotein (LDL-C))
Time frame: Baseline to 6 months
Change in Lipid Profile (Triglycerides)
Time frame: Baseline to 6 months
Change in Lipid Profile (Oxidized LDL)
Time frame: Baseline to 6 months
Change in Health Related Quality of Life Score (Short Form (SF-36))
Time frame: Baseline to 6 months
Change in Dietary Intake Levels of Long-chain Polyunsaturated Fatty Acids (LC-PUFA ) (i.e. DHA and EPA) as Measured by the Food Frequency Questionnaire (FFQ)
Time frame: Baseline to 6 months
Change in Inflammatory Markers (Cytokeratin 18 (CK-18))
Time frame: Baseline to 6 months
Change in Inflammatory Markers (IL-1β)
Time frame: Baseline to 6 months
Change in Inflammatory Markers (TNFα)
Time frame: Baseline to 6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 May 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Naga P. Chalasani, MD principal investigator
Indiana University
15 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Vitamin E [(all-rac)-α-tocopheryl acetate], Omega-3 fatty acid (DHA EE) and Omega-3 fatty acid (DHA EE) & Vitamin E [(all-rac)-α-tocopheryl acetate] in people with Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Fatty Liver, run by Naga P. Chalasani at 15 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 15 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 May 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Hepatic Fat Fraction [%] Between of Vitamin E and DHA EE vs Placebo (time frame: Baseline to 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 May 2023.