Fatty LiverPhase 2NCT00323414
Polyunsaturated Fatty Acids (PUFA) in Diabetic Fatty Liver
A Phase 2 study testing Polyunsaturated fatty acid (Opti-EPA) in people with Fatty Liver, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 2 sites in United States.
Trial summary
Non-alcoholic steatohepatitis (NASH), the most severe form of liver injury in the spectrum of non-alcoholic fatty liver disease (NAFLD), has emerged as the major cause of chronic liver disease in developed countries. Among adults in the United States, the prevalence is between 5.7% and 17%. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Fatty Liver
- What is being tested?
- Polyunsaturated fatty acid (Opti-EPA)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 37 participants
- Where
- 2 sitesUnited States
- Study dates
- Apr 2006to Dec 2011
- 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
- Adult patients (age >18 years)
- Have type 2 diabetes mellitus with good control of blood sugar (hemoglobin A1c [HbA1c] <7.5%) and will have been on a stable regimen of anti-diabetic agents for more than 4 months.
- NASH established on liver biopsy done within 6 months prior to inclusion in the study as determined by established histologic criteria
Who cannot join
- Cirrhosis of the liver
- End stage target organ damage in diabetes mellitus: advanced renal failure (serum creatinine > 2.0 mg/dl) with or without dialysis, severe neuropathy, or advanced peripheral vascular disease.
- Any organ dysfunction with anticipated life expectancy of less than 2 years
- Co-existent etiologies for liver disease
- Significant alcohol consumption, defined as more than 30 g per day in men and more than 20 g per day in women.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
MetroHealth Medical Center
Cleveland, Ohio, 44109
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
About this study
Official title: Randomized Controlled Trial of Omega-3 Fatty Acids in the Treatment of Non-Alcoholic Steatohepatitis in Patients With Type 2 Diabetes Mellitus
Non-alcoholic steatohepatitis (NASH), the most severe form of liver injury in the spectrum of non-alcoholic fatty liver disease (NAFLD), has emerged as the major cause of chronic liver disease in developed countries. Among adults in the United States, the prevalence is between 5.7% and 17%. These rates are expected to increase concurrent with the epidemics of obesity and type 2 diabetes mellitus, which are the major risk factors for NAFLD and NASH. In addition to its high prevalence, NASH is also a progressive fibrotic disease that advances to cirrhosis and liver related death in 20% and 12% of patients, respectively. Among NASH patients with cirrhosis, 40% have liver related death. Diabetics are particularly prone to experience these poor outcomes. No therapy has been proven effective for patients with NASH.
The purpose of this study is to find out whether treatment with polyunsaturated fatty acids (eicosapentaenoic acid [EPA] combined with docosahexaenoic acid [DHA] called Opti-EPA) improves NASH compared to treatment with placebo pills. The placebo pills will contain corn oil and will be contained in a capsule, but have no medical effect on the body. The investigators will determine improvement in NASH from microscopic changes in the subject's liver tissue during 48 weeks of treatment. This means that the subject will need to have a liver biopsy before and after the treatment.
Read more
Omega-3 fatty acids are a form of polyunsaturated fats, one of the four basic types of fat that the body gets from food. (Cholesterol, saturated fat, and monounsaturated fat are the others.) One's body does not make this type of fat; it comes from food sources. These fats are found in foods like cold water fish (tuna, salmon, and mackerel), and vegetable products like flaxseed oil and walnuts.
Research shows that polyunsaturated fats are good for people. Studies have shown that it is good for heart health by playing a role in keeping blood cholesterol levels low, keeping irregular heart rhythms stable, and reducing blood pressure.
The drug being studied, Opti-EPA, is a nutritional supplement. They do not have to be reviewed by the Food and Drug Administration (FDA) like medicines do. Opti-EPA is considered experimental in this study. This means that the United States Food and Drug Administration (FDA) has not approved it for use in people with nonalcoholic fatty liver disease.
Read the detailed description
Although there is no proven effective treatment of NASH, dietary supplementation with long chain omega-3 polyunsaturated fatty acids (PUFA's) may be beneficial. This suggestion is based on three previously reported observations: first, patients with NASH consume less PUFAs and more saturated fats than subjects without NASH. Second, PUFAs are beneficial in patients with hypertension and hypertriglyceridemia. Third, PUFAs decrease lipid peroxidation and ameliorate hepatic steatosis in animal models of NAFLD.
We therefore hypothesize that the administration of these PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) will reduce hepatic fat content, inflammation and hepatic injury in patients with type 2 diabetes mellitus who have NASH.
Aims
To determine in patients with type 2 diabetes mellitus who have NASH if dietary supplementation with purified omega-3 fatty acids (EPA and DHA) will:
- Decrease the histologic severity of NASH.
- Alter the expression of genes important in the pathways of hepatic lipid synthesis and oxidation.
Study design:
Patients who meet the inclusion criteria will be randomized to receive omega-3 fatty acids or placebo. Stratified randomization will be done based on the NASH Clinical Research Network pathology score of 5.
- Conditions
- Fatty Liver
- Being tested
- Polyunsaturated fatty acid (Opti-EPA), Placebo
- Keywords
- PUFA, NASH, Fatty Liver, Insulin resistance, Metabolic syndrome, Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, Type 2 Diabetes Mellitus
- Medical subject headings
- Fatty Liver, Insulin Resistance, Metabolic Syndrome, Non-alcoholic Fatty Liver Disease, Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Polyunsaturated fatty acid (Opti-EPA)Drug
Also called Fish oil
Active experimental arm to patients with diabetes mellitus and non alcoholic steatohepatitis: Eicosapentaenoic acid (EPA):Docosahexaenoic acid (DHA)[360 mg EPA and 240 DHA in each capsule] 6 capsules-3 capsules by mouth 2 x per day x 48 weeks
PlaceboDrug
Also called Corn oil
Placebo gelcaps containing corn oil identical to the PUFA gelcaps 6 capsules-3 capsules by mouth 2x per day x 48 weeks
| Study group | Role | What they receive |
|---|---|---|
| Polyunsaturated fatty acid (Opti-EPA) | Active comparator | Polyunsaturated fatty acid will consist of purified EPA:DHA (360 mg EPA and 240 mg DHA) 6 gelcaps-3 capsules by mouth 2x per day x 48 weeks Receives: Drug: Polyunsaturated fatty acid (Opti-EPA) |
| Placebo | Placebo comparator | Gelcaps containing corn oil as placebo 6 capsules 3 capsules by mouth 2 x per day for 48 weeks Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Improvement of >= 2 Points in NAFLD Activity Score (NAS)
The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) is a score based on the liver biopsy. It represents the sum of scores for steatosis, lobular inflammation, and ballooning, and ranges from 0-8, with high scores indicating more activity.
Measured: 48 weeks
Secondary outcomes (5)
Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) Values
Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) measures insulin resistance, calculated by fasting insulin (μU/mL) multiplied by fasting glucose (mg/dL), and divided by a constant (405). A higher score indicates higher insulin resistance.
Measured: 48 weeks
Aspartate Amino Transferase (AST) Levels
Aspartate amino transferase (IU/dL) at 48 weeks
Measured: 48 weeks
Alanine Amino Transferase (ALT) Levels
Alanine amino transferase (IU/dL) ay 48 weeks
Measured: 48 weeks
Blood Glucose Levels
Fasting blood glucose
Measured: 48 weeks
HbA1C Levels
Hemoglobin A1c
Measured: 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2006 (estimated)
- Study startApr 2006
- Primary completionDec 2011
- Study completionDec 2011
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.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Fatty LiverStudies of the same condition, open and under way.
- More trials run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)The sponsor's other registered studies.
- 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
- 37 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Arthur J. McCullough, M.D., Principal investigator, MetroHealth Medical CenterSrinivasan Dasarathy, M.D., Principal investigator, The Cleveland Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00323414
- Sponsor's protocol ID
- DK61732
- Other IDs
- U01DK061732
- Status last verified
- Oct 2017
- First submitted
- 5 May 2006
- Last updated
- 23 Feb 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2004 Mar;2(3):262-5. doi: 10.1016/s1542-3565(04)00014-x.
PubMed 15017611Dasarathy S, Dasarathy J, Khiyami A, Yerian L, Hawkins C, Sargent R, McCullough AJ. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J Clin Gastroenterol. 2015 Feb;49(2):137-44. doi: 10.1097/MCG.0000000000000099.
PubMed 24583757
Study at a glance
From the registry record, last updated by the sponsor on 23 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Controlled Trial of Omega-3 Fatty Acids in the Treatment of Non-Alcoholic Steatohepatitis in Patients With Type 2 Diabetes Mellitus
- ClinicalTrials.gov ID
- NCT00323414
- Acronym / sponsor ID
- DK61732
- Conditions
- Fatty Liver
- Keywords
- PUFA, NASH, Fatty Liver, Insulin resistance, Metabolic syndrome, Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, Type 2 Diabetes Mellitus
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 37 participants (actual)
- Lead sponsor
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)US National Institutes of Health
- Study start
- Apr 2006
- Primary completion
- Dec 2011 (actual)
- Study completion
- Dec 2011 (actual)
- First posted
- 9 May 2006 (estimated)
- Results
- Posted 23 Feb 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Non-alcoholic steatohepatitis (NASH), the most severe form of liver injury in the spectrum of non-alcoholic fatty liver disease (NAFLD), has emerged as the major cause of chronic liver disease in developed countries. Among adults in the United States, the prevalence is between 5.7% and 17%. These rates are expected to increase concurrent with the epidemics of obesity and type 2 diabetes mellitus, which are the major risk factors for NAFLD and NASH. In addition to its high prevalence, NASH is also a progressive fibrotic disease that advances to cirrhosis and liver related death in 20% and 12% of patients, respectively. Among NASH patients with cirrhosis, 40% have liver related death. Diabetics are particularly prone to experience these poor outcomes. No therapy has been proven effective for patients with NASH.
The purpose of this study is to find out whether treatment with polyunsaturated fatty acids (eicosapentaenoic acid [EPA] combined with docosahexaenoic acid [DHA] called Opti-EPA) improves NASH compared to treatment with placebo pills. The placebo pills will contain corn oil and will be contained in a capsule, but have no medical effect on the body. The investigators will determine improvement in NASH from microscopic changes in the subject's liver tissue during 48 weeks of treatment. This means that the subject will need to have a liver biopsy before and after the treatment.
Omega-3 fatty acids are a form of polyunsaturated fats, one of the four basic types of fat that the body gets from food. (Cholesterol, saturated fat, and monounsaturated fat are the others.) One's body does not make this type of fat; it comes from food sources. These fats are found in foods like cold water fish (tuna, salmon, and mackerel), and vegetable products like flaxseed oil and walnuts.
Research shows that polyunsaturated fats are good for people. Studies have shown that it is good for heart health by playing a role in keeping blood cholesterol levels low, keeping irregular heart rhythms stable, and reducing blood pressure.
The drug being studied, Opti-EPA, is a nutritional supplement. They do not have to be reviewed by the Food and Drug Administration (FDA) like medicines do. Opti-EPA is considered experimental in this study. This means that the United States Food and Drug Administration (FDA) has not approved it for use in people with nonalcoholic fatty liver disease.
Detailed description
Although there is no proven effective treatment of NASH, dietary supplementation with long chain omega-3 polyunsaturated fatty acids (PUFA's) may be beneficial. This suggestion is based on three previously reported observations: first, patients with NASH consume less PUFAs and more saturated fats than subjects without NASH. Second, PUFAs are beneficial in patients with hypertension and hypertriglyceridemia. Third, PUFAs decrease lipid peroxidation and ameliorate hepatic steatosis in animal models of NAFLD.
We therefore hypothesize that the administration of these PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) will reduce hepatic fat content, inflammation and hepatic injury in patients with type 2 diabetes mellitus who have NASH.
Aims
To determine in patients with type 2 diabetes mellitus who have NASH if dietary supplementation with purified omega-3 fatty acids (EPA and DHA) will:
- Decrease the histologic severity of NASH.
- Alter the expression of genes important in the pathways of hepatic lipid synthesis and oxidation.
Study design:
Patients who meet the inclusion criteria will be randomized to receive omega-3 fatty acids or placebo. Stratified randomization will be done based on the NASH Clinical Research Network pathology score of 5.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Polyunsaturated fatty acid (Opti-EPA) | Active comparator | Drug: Polyunsaturated fatty acid (Opti-EPA)Polyunsaturated fatty acid will consist of purified EPA:DHA (360 mg EPA and 240 mg DHA) 6 gelcaps-3 capsules by mouth 2x per day x 48 weeks |
| Placebo | Placebo comparator | Drug: PlaceboGelcaps containing corn oil as placebo 6 capsules 3 capsules by mouth 2 x per day for 48 weeks |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Adult patients (age >18 years)
- Have type 2 diabetes mellitus with good control of blood sugar (hemoglobin A1c [HbA1c] <7.5%) and will have been on a stable regimen of anti-diabetic agents for more than 4 months.
- NASH established on liver biopsy done within 6 months prior to inclusion in the study as determined by established histologic criteria
Key exclusion criteria (5 listed)
- Cirrhosis of the liver
- End stage target organ damage in diabetes mellitus: advanced renal failure (serum creatinine > 2.0 mg/dl) with or without dialysis, severe neuropathy, or advanced peripheral vascular disease.
- Any organ dysfunction with anticipated life expectancy of less than 2 years
- Co-existent etiologies for liver disease
- Significant alcohol consumption, defined as more than 30 g per day in men and more than 20 g per day in women.
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 |
|---|---|---|
| Polyunsaturated fatty acid (Opti-EPA)Also: Fish oilActive experimental arm to patients with diabetes mellitus and non alcoholic steatohepatitis: Eicosapentaenoic acid (EPA):Docosahexaenoic acid (DHA)[360 mg EPA and 240 DHA in each capsule] 6 capsules-3 capsules by mouth 2 x per day x 48 weeks | Drug | Polyunsaturated fatty acid (Opti-EPA) |
| PlaceboAlso: Corn oilPlacebo gelcaps containing corn oil identical to the PUFA gelcaps 6 capsules-3 capsules by mouth 2x per day x 48 weeks | Drug | Placebo |
Primary outcome
Number of Participants With Improvement of >= 2 Points in NAFLD Activity Score (NAS)
Time frame: 48 weeks
The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) is a score based on the liver biopsy. It represents the sum of scores for steatosis, lobular inflammation, and ballooning, and ranges from 0-8, with high scores indicating more activity.
5 secondary outcomes
Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) Values
Time frame: 48 weeks
Aspartate Amino Transferase (AST) Levels
Time frame: 48 weeks
Alanine Amino Transferase (ALT) Levels
Time frame: 48 weeks
Blood Glucose Levels
Time frame: 48 weeks
HbA1C Levels
Time frame: 48 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Feb 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 15017611Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2004 Mar;2(3):262-5. doi: 10.1016/s1542-3565(04)00014-x.
- Derived from this study: PubMed 24583757Dasarathy S, Dasarathy J, Khiyami A, Yerian L, Hawkins C, Sargent R, McCullough AJ. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J Clin Gastroenterol. 2015 Feb;49(2):137-44. doi: 10.1097/MCG.0000000000000099.
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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.
Arthur J. McCullough, M.D. principal investigator
MetroHealth Medical Center
Srinivasan Dasarathy, M.D. principal investigator
The Cleveland Clinic
2 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 Polyunsaturated fatty acid (Opti-EPA) in people with Fatty Liver, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 2 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 3 inclusion and 5 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 23 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 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 23 Feb 2018). 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?
Number of Participants With Improvement of >= 2 Points in NAFLD Activity Score (NAS) (time frame: 48 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00323414, which also lists 2 linked publications.
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 23 Feb 2018.