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Double-Blind, Placebo-Controlled Study of Two Doses of EPA-E in Patients With Non Alcoholic Steatohepatitis (NASH)

A Phase II Double-Blind, Placebo-Controlled Study of Two Doses of EPA-E in Patients With NASH

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT01154985
Enrollment
243
Registered
2010-07-01
Start date
2010-06-30
Completion date
2012-10-31
Last updated
2014-11-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Steatohepatitis

Keywords

omega-3 fatty acids, alanine transaminase, triglycerides, lipids, EPA, ethyl-EPA, ethyl icosapentate, Non Alcoholic steatohepatitis, Non Alcoholic fatty liver disease, fatty acids

Brief summary

This is a controlled study to determine the effectiveness and safety of ethyl icosapentate (EPA-E) in the treatment of adult patients with non-alcoholic steatohepatitis (NASH).

Detailed description

This is a phase II, double-blinded, placebo-controlled study to investigate the safety, efficacy, and pharmacokinetic profile of two doses of EPA-E in adult subjects with NASH. Subjects are required to have a liver biopsy with proven NASH in the 6 month period prior to screening. Up to 70 subjects will be enrolled into each treatment arm in a 1:1:1 ratio, for a total of 210 subjects. Subjects will be stratified at randomization by presence or absence of diabetes. Duration of treatment is 12 months.

Interventions

DRUGPlacebo capsule

3x Placebo capsules three times a day (TID) for 365 days

DRUGEPA-E 300 mg capsule

2x 300 mg capsules + placebo capsule TID for 365 days

Sponsors

Mochida Pharmaceutical Company, Ltd.
Lead SponsorINDUSTRY

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

* Diagnosis of definite NASH * Patients with diabetes taking stable doses of anti-diabetic agents are eligible * No significant concomitant medical illness

Exclusion criteria

* Diagnosis of cirrhosis. * Serum ALT \> 300 U/L * Use of drugs associated with steatohepatitis * Use of the following anit-NASH agents: 1. Vitamin E \> 60 IU per day 2. Omega-3-acid ethyl esters or omega-3-polyunsaturated fatty acid (PUFA)-containing supplements \> 200 mg per day 3. Thiazolidinediones (e.g. pioglitazone) * Use of non-stable doses of the following anti-NASH agents: HMGCoA reductase inhibitors (statins), fibrates, probucol, ezetimibe, ursodiol (UDCA), taurine, betaine, N-acetylcysteine, s-adenosylmethionine (SAM-E), milk thistle, anti-TNF therapies, or probiotics. * Other liver disease

Design outcomes

Primary

MeasureTime frameDescription
Histological Response Defined by Change From Baseline in Standardized Scoring of Liver Biopsies12 monthsPatient is considered a responder if histological examination shows: Composite NAS of \<=3 AND no worsening in Fibrosis OR Improvement in NAS by \>=2 across at least 2 of the NAS components AND no worsening in fibrosis A priori threshold for statistical significance is p\<0.05, 1-sided
Alanine Transaminase (ALT) Levels3 month endpointMean change from baseline at month 3 analyzed by Analysis of Covariance (ANCOVA) in the efficacy evaluable analysis set with treatment group as a factor and baseline ALT as a covariate. Principal comparisons were the response between; 1. EPA-E 2700 mg and Placebo groups 2. EPA-E 1800 mg and Placebo groups

Countries

Puerto Rico, United States

Participant flow

Participants by arm

ArmCount
Placebo
Placebo: Placebo three times a day (TID) for 365 days
75
EPA-E 1800 mg/Day
EPA-E: 600 mg TID for 365 days
82
EPA-E 2700 mg/Day
EPA-E: 900 mg TID for 365 days
86
Total243

Baseline characteristics

CharacteristicPlaceboEPA-E 1800 mg/DayEPA-E 2700 mg/DayTotal
Age, Categorical
<=18 years
0 Participants0 Participants0 Participants0 Participants
Age, Categorical
>=65 years
8 Participants8 Participants6 Participants22 Participants
Age, Categorical
Between 18 and 65 years
67 Participants74 Participants80 Participants221 Participants
Age, Continuous50.5 years
STANDARD_DEVIATION 12.45
47.8 years
STANDARD_DEVIATION 12.48
47.8 years
STANDARD_DEVIATION 11.14
48.6 years
STANDARD_DEVIATION 12.02
Ethnicity (NIH/OMB)
Hispanic or Latino
15 Participants15 Participants15 Participants45 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
60 Participants67 Participants71 Participants198 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants1 Participants2 Participants3 Participants
Race (NIH/OMB)
Asian
3 Participants1 Participants6 Participants10 Participants
Race (NIH/OMB)
Black or African American
3 Participants3 Participants2 Participants8 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
1 Participants0 Participants1 Participants2 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
White
68 Participants77 Participants75 Participants220 Participants
Sex: Female, Male
Female
43 Participants48 Participants57 Participants148 Participants
Sex: Female, Male
Male
32 Participants34 Participants29 Participants95 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
deaths
Total, all-cause mortality
— / —— / —— / —
other
Total, other adverse events
71 / 7565 / 8274 / 86
serious
Total, serious adverse events
4 / 758 / 825 / 86

Outcome results

Primary

Alanine Transaminase (ALT) Levels

Mean change from baseline at month 3 analyzed by Analysis of Covariance (ANCOVA) in the efficacy evaluable analysis set with treatment group as a factor and baseline ALT as a covariate. Principal comparisons were the response between; 1. EPA-E 2700 mg and Placebo groups 2. EPA-E 1800 mg and Placebo groups

Time frame: 3 month endpoint

Population: Efficacy Evaluable Analysis Set - All patients in Full Analysis Set who have valid 12-month histological data without major protocol violations, including withdrawn patients with valid 12.5 month histological data after more than 6 months treatment

ArmMeasureValue (LEAST_SQUARES_MEAN)Dispersion
PlaceboAlanine Transaminase (ALT) Levels-19.3 U/LStandard Error 4.61
EPA-E 1800 mg/DayAlanine Transaminase (ALT) Levels-3.0 U/LStandard Error 4.61
EPA-E 2700 mg/DayAlanine Transaminase (ALT) Levels2.8 U/LStandard Error 4.27
Comparison: Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 1,800 mg/day EPA-E treatment group compared to placebo.p-value: 0.0137ANCOVA
Comparison: Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 1,800 mg/day EPA-E treatment group compared to placebo.95% CI: [3.4, 29.1]
Comparison: Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 2,700 mg/day EPA-E treatment group compared to placebo.p-value: 0.0006ANCOVA
Comparison: Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 2,700 mg/day EPA-E treatment group compared to placebo.95% CI: [9.6, 34.4]
Primary

Alanine Transaminase (ALT) Levels

Mean change from baseline at month 6 analyzed by Analysis of Covariance (ANCOVA) in the efficacy analysis set with treatment group as a factor and baseline ALT as a covariate. Principal comparisons were the response between; 1. EPA-E 2700 mg and Placebo groups 2. EPA-E 1800 mg and Placebo groups

Time frame: 6 months

Population: Efficacy Evaluable Analysis Set - All patients in Full Analysis Set who have valid 12-month histological data without major protocol violations, including withdrawn patients with valid 12.5 month histological data after more than 6 months treatment

ArmMeasureValue (MEAN)Dispersion
PlaceboAlanine Transaminase (ALT) Levels-19.1 U/LStandard Deviation 4.79
EPA-E 1800 mg/DayAlanine Transaminase (ALT) Levels-9.5 U/LStandard Deviation 4.8
EPA-E 2700 mg/DayAlanine Transaminase (ALT) Levels-3.0 U/LStandard Deviation 4.45
Comparison: Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 1,800 mg/day EPA-E treatment group compared to placebo.p-value: 0.1592ANCOVA
Comparison: Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 1,800 mg/day EPA-E treatment group compared to placebo.95% CI: [-3.8, 23]
Comparison: Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 2,700 mg/day EPA-E treatment group compared to placebo.p-value: 0.0153ANCOVA
Comparison: Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 2,700 mg/day EPA-E treatment group compared to placebo.95% CI: [3.1, 28.9]
Primary

Histological Response Defined by Change From Baseline in Standardized Scoring of Liver Biopsies

Patient is considered a responder if histological examination shows: Composite NAS of \<=3 AND no worsening in Fibrosis OR Improvement in NAS by \>=2 across at least 2 of the NAS components AND no worsening in fibrosis A priori threshold for statistical significance is p\<0.05, 1-sided

Time frame: 12 months

Population: Efficacy Evaluable Analysis Set - All patients in Full Analysis Set who have valid 12-month histological data without major protocol violations, including withdrawn patients with valid 12.5 month histological data after more than 6 months treatment

ArmMeasureValue (NUMBER)
PlaceboHistological Response Defined by Change From Baseline in Standardized Scoring of Liver Biopsies18 participants
EPA-E 1800 mg/DayHistological Response Defined by Change From Baseline in Standardized Scoring of Liver Biopsies18 participants
EPA-E 2700 mg/DayHistological Response Defined by Change From Baseline in Standardized Scoring of Liver Biopsies20 participants
Comparison: Proportion of responders in the EPA-E 1800 mg and 2700 mg groups compared to the proportion of responders in the placebo group compared using the Cochran-Armitage trend test in the Efficacy Evaluable analysis set. P-value less than 5% 1-sided. A total sample size of 210 (70 per arm) was planned to give 80% power for detecting a positive dose-response slope among the 3 treatment arms at 12 months.p-value: 0.57Cochran-Armitage trend test

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026