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Vitamin E and DHA-EE on NAFLD - Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Clinical Trial (PUVENAFLD) (PUVENAFLD)

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ClinicalTrials.gov Identifier: NCT04198805
Recruitment Status : Recruiting
First Posted : December 13, 2019
Last Update Posted : July 29, 2020
Sponsor:
Collaborator:
DSM Nutritional Products, Inc.
Information provided by (Responsible Party):
Naga P. Chalasani, Indiana University School of Medicine

Brief 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. 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.

Condition or disease Intervention/treatment Phase
Non-Alcoholic Fatty Liver Disease Non-Alcoholic Fatty Liver Non-Alcoholic Steatohepatitis Dietary Supplement: Vitamin E [(all-rac)-α-tocopheryl acetate] Dietary Supplement: Omega-3 fatty acid (DHA EE) Combination Product: Omega-3 fatty acid (DHA EE) & Vitamin E [(all-rac)-α-tocopheryl acetate] Other: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)
Actual Study Start Date : January 3, 2020
Estimated Primary Completion Date : June 1, 2021
Estimated Study Completion Date : December 1, 2022


Arm Intervention/treatment
Active Comparator: Vitamin E (1000 mg)
Vitamin E (1000 mg) once daily for 6 months (1 capsule) and matching placebos (2 matched capsules) for 6 months.
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

Active Comparator: DHA EE (1.89 g)
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: 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)

Active Comparator: DHA EE (1.89 g) and Vitamin E (1000 mg)
DHA EE (1.89 g) once daily for 6 months and Vitamin E (1000 mg) once daily for 6 months.
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
Other Name: Vitamin E [(all-rac)-α-tocopheryl acetate]

Placebo Comparator: Placebo
Matching soybean oil placebo (3 capsules) of all arms daily for 6 months.
Other: Placebo
Matching soybean placebo (3 capsules) of all arms daily for 6 months.




Primary Outcome Measures :
  1. Decrease in hepatic fat fraction [%] between Vitamin E + DHA combination vs placebo arm [ Time Frame: Baseline to 6 months ]
    The number of subjects a change in liver fat content relative to baseline between Vitamin E + DHA combination vs placebo arm. This will be measured by MRI-PDFF at baseline and after 6 months of intervention.


Secondary Outcome Measures :
  1. Decrease in hepatic fat fraction [%] between Vitamin E vs placebo arm [ Time Frame: Baseline to 6 months ]
    The number of subjects with a 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.

  2. Decrease in hepatic fat fraction [%] between DHA EE vs placebo arm [ Time Frame: Baseline to 6 months ]
    The number of subjects with a 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.

  3. Change after 6 months of DHA EE and/ or Vitamin E intervention in the anthropometric measure, waist circumference. [ Time Frame: Baseline to 6 months ]
    Evaluation of baseline and 6 month measurements of waist circumference in the DHA EE and /or Vitamin E intervention over a 6 month period.

  4. Change after 6 months of DHA EE and/ or Vitamin E intervention in the anthropometric measure, bodyweight. [ Time Frame: Baseline to 6 months ]
    Evaluation of baseline and 6-month measurements of body weight in the DHA EE and /or Vitamin E intervention over a 6 month period.

  5. 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 ]
    Evaluation of baseline and 6-month measurements of waist-to-hip ratio in the DHA EE and /or Vitamin E intervention over a 6 month period.

  6. 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 ]
    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.

  7. Insulin resistance [ Time Frame: Baseline to 6 months ]
    The number of subjects with insulin resistance in the DHA EE and /or Vitamin E intervention over a 6 month period.

  8. Liver enzymes (ALT, AST, Albumin, Bilirubin, GGT, Alkaline Phosphatase and Creatinine) [ Time Frame: Baseline to 6 months ]
    Evaluation of baseline and 6-month liver enzymes: alanine transaminase (ALT), aspartate transaminase (AST), bilirubin, Gamma-glutamyltransferase (GGT), creatinine, and Alkaline phosphatase (AKP) in the DHA EE and /or Vitamin E intervention over a 6 month period.

  9. Fibrosis-4 (FIB-4) score [ Time Frame: Baseline to 6 months ]
    The number of subjects with fibrosis-4 (FIB-4) score in the DHA EE and /or Vitamin E intervention over a 6 month period.

  10. Plasma Vitamin E concentration [ Time Frame: Baseline to 6 months ]
    Evaluation of baseline and 6-month plasma Vitamin E concentration in the DHA EE and /or Vitamin E intervention over a 6 month period.

  11. Plasma DHA EE concentration [ Time Frame: Baseline to 6 months ]
    Evaluation of baseline and 6-month plasma DHA EE concentration in the DHA EE and /or Vitamin E intervention over a 6 month period.

  12. Lipid profile (e.g. HDL-C, low density lipoprotein (LDL-C), TGs, oxidized LDL) [ Time Frame: Baseline to 6 months ]
    Evaluation of baseline and 6-month lipid profile (e.g. HDL-C, low density lipoprotein (LDL-C), TGs, oxidized LDL)in the DHA EE and /or Vitamin E intervention over a 6 month period.

  13. Health related quality of life score (Short form (SF-36)) [ Time Frame: Baseline to 6 months ]
    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.

  14. Dietary Intake Levels of LC-PUFA (i.e. DHA and EPA) as measured by the Food Frequency Questionnaire (FFQ) [ Time Frame: Baseline to 6 months ]
    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.

  15. Inflammatory markers (e.g. cytokeratin 18 (CK-18), TNFα, IL-1β) [ Time Frame: Baseline to 6 months ]
    Evaluation of baseline and 6-month inflammatory markers (e.g. cytokeratin 18 (CK-18), TNFα, IL-1β) in the DHA EE and /or Vitamin E intervention over a 6 month period.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • 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≥ 45 U/L
  • 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

Exclusion Criteria:

  • 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%
  • 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, 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

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): NCT04198805


Contacts
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Contact: Kayla Gelow, BS (317) 278-9226 peterkay@iu.edu
Contact: Julianne Nanzer, BS (317) 278-9291 jnanzer@iu.edu

Locations
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United States, Arkansas
Arkansas Gastroenterology Recruiting
North Little Rock, Arkansas, United States, 72117
Contact: Stephanie Hunter    501-945-9300    stephaniehogue@arkgi.net   
Principal Investigator: Johnathan Goodwin, MD         
United States, California
Inland Empire Clinical Trials, LLC Recruiting
Rialto, California, United States, 92377
Contact: Nazly Amaya    909-644-4058    namaya@ieliverfoundation.com   
Principal Investigator: Zeid Kayali, MD         
United States, Florida
Integrity Clinical Research LLC Recruiting
Doral, Florida, United States, 33166
Contact: Miguel Dempere    305-552-7660    mdempere@icrsites.com   
Principal Investigator: Linda Martinez, MD         
Advanced Pharma CR LLC Recruiting
Miami, Florida, United States, 33147
Contact: Ivette Lopez    305-220-2727 ext 803    ilopez@advancedpharmacr.com   
Principal Investigator: Kimberly Cruz, MD         
United States, Georgia
Summit Clinical Research LLC Recruiting
Athens, Georgia, United States, 30607
Contact: Kelly Peppers    706-400-4262    kpeppers@summitclinicalstudies.com   
Principal Investigator: Jeffrey Williams, MD         
United States, Indiana
Indiana University School of Medicine Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Stacey Richardson, BSN    317-278-9215    stlyrich@iu.edu   
Principal Investigator: Naga Chalasani, MD         
United States, North Carolina
M3 Wake Research Associates Recruiting
Raleigh, North Carolina, United States, 27612
Contact: Amanda Salisbury    919-781-2514    asalisbury@wakeresearch.com   
Principal Investigator: Bulent Ender, MD         
United States, Texas
Centex Studies, Inc. Recruiting
Houston, Texas, United States, 77058
Contact: Jenna Anastasiades    281-282-0808    jenna@centexstudies.com   
Principal Investigator: Joe Pouzar Jr., MD         
American Research Corporation at the Texas Liver Institute Recruiting
San Antonio, Texas, United States, 78215
Contact: Shanen Jaca    210-253-3426    sjaca@txliver.com   
Principal Investigator: Eric Lawitz, MD         
Sponsors and Collaborators
Naga P. Chalasani
DSM Nutritional Products, Inc.
Investigators
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Principal Investigator: Naga P. Chalasani, MD Indiana University School of Medicine
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Responsible Party: Naga P. Chalasani, Associate Dean of Research, Director of GI/Hepatology, Indiana University School of Medicine
ClinicalTrials.gov Identifier: NCT04198805    
Other Study ID Numbers: 2017-1088
First Posted: December 13, 2019    Key Record Dates
Last Update Posted: July 29, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Time Frame: April, 2024

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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 Naga P. Chalasani, Indiana University School of Medicine:
Non-Alcoholic Fatty Liver Disease
Non-Alcoholic Fatty Liver
NAFL
NAFLD
Vitamin E
DHA
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases
Vitamins
Vitamin E
Tocopherols
Tocotrienols
alpha-Tocopherol
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents