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

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ClinicalTrials.gov Identifier: NCT01154985
Recruitment Status : Completed
First Posted : July 1, 2010
Results First Posted : November 20, 2014
Last Update Posted : November 20, 2014
Sponsor:
Information provided by (Responsible Party):
Mochida Pharmaceutical Company, Ltd.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Steatohepatitis
Interventions Drug: Placebo capsule
Drug: EPA-E 300 mg capsule
Enrollment 243
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo EPA-E 1800 mg/Day EPA-E 2700 mg/Day
Hide Arm/Group Description Placebo: Placebo three times a day (TID) for 365 days EPA-E: 600 mg TID for 365 days EPA-E: 900 mg TID for 365 days
Period Title: Overall Study
Started 75 [1] 82 [1] 86 [1]
Full Analysis Set 75 [2] 82 [2] 86 [2]
Valid Biopsy -Baseline and Month 12.5 60 62 68
Efficacy Evaluable Analysis Set 55 [3] 55 [3] 64 [3]
Completed 58 55 68
Not Completed 17 27 18
[1]
Randomized
[2]
Received at least one dose of study medication
[3]
12-months histological data, no major protocol violations; after minimum 6 months treatment
Arm/Group Title Placebo EPA-E 1800 mg/Day EPA-E 2700 mg/Day Total
Hide Arm/Group Description Placebo: Placebo three times a day (TID) for 365 days EPA-E: 600 mg TID for 365 days EPA-E: 900 mg TID for 365 days Total of all reporting groups
Overall Number of Baseline Participants 75 82 86 243
Hide Baseline Analysis Population Description
Full Analysis Set
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 75 participants 82 participants 86 participants 243 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
67
  89.3%
74
  90.2%
80
  93.0%
221
  90.9%
>=65 years
8
  10.7%
8
   9.8%
6
   7.0%
22
   9.1%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 75 participants 82 participants 86 participants 243 participants
50.5  (12.45) 47.8  (12.48) 47.8  (11.14) 48.6  (12.02)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 75 participants 82 participants 86 participants 243 participants
Female
43
  57.3%
48
  58.5%
57
  66.3%
148
  60.9%
Male
32
  42.7%
34
  41.5%
29
  33.7%
95
  39.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 75 participants 82 participants 86 participants 243 participants
Hispanic or Latino
15
  20.0%
15
  18.3%
15
  17.4%
45
  18.5%
Not Hispanic or Latino
60
  80.0%
67
  81.7%
71
  82.6%
198
  81.5%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 75 participants 82 participants 86 participants 243 participants
American Indian or Alaska Native
0
   0.0%
1
   1.2%
2
   2.3%
3
   1.2%
Asian
3
   4.0%
1
   1.2%
6
   7.0%
10
   4.1%
Native Hawaiian or Other Pacific Islander
1
   1.3%
0
   0.0%
1
   1.2%
2
   0.8%
Black or African American
3
   4.0%
3
   3.7%
2
   2.3%
8
   3.3%
White
68
  90.7%
77
  93.9%
75
  87.2%
220
  90.5%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Histological Response Defined by Change From Baseline in Standardized Scoring of Liver Biopsies
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Placebo EPA-E 1800 mg/Day EPA-E 2700 mg/Day
Hide Arm/Group Description:
Placebo: Placebo three times a day (TID) for 365 days
EPA-E: 600 mg TID for 365 days
EPA-E: 900 mg TID for 365 days
Overall Number of Participants Analyzed 55 55 64
Measure Type: Number
Unit of Measure: participants
18 18 20
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, EPA-E 1800 mg/Day, EPA-E 2700 mg/Day
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.57
Comments [Not Specified]
Method Cochran-Armitage trend test
Comments [Not Specified]
2.Primary Outcome
Title Alanine Transaminase (ALT) Levels
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Placebo EPA-E 1800 mg/Day EPA-E 2700 mg/Day
Hide Arm/Group Description:
Placebo: Placebo three times a day (TID) for 365 days
EPA-E: 600 mg TID for 365 days
EPA-E: 900 mg TID for 365 days
Overall Number of Participants Analyzed 55 55 64
Least Squares Mean (Standard Error)
Unit of Measure: U/L
-19.3  (4.61) -3.0  (4.61) 2.8  (4.27)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, EPA-E 1800 mg/Day
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0137
Comments Two-sided p-values testing for significance was performed within treatment group change from baseline and comparisons between treatment groups. Multiple comparison techniques were not applied.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, EPA-E 1800 mg/Day
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 16.2
Confidence Interval (2-Sided) 95%
3.4 to 29.1
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, EPA-E 2700 mg/Day
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments Two-sided p-values testing for significance was performed within treatment group change from baseline and comparisons between treatment groups. Multiple comparison techniques were not applied.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, EPA-E 2700 mg/Day
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 22.0
Confidence Interval (2-Sided) 95%
9.6 to 34.4
Estimation Comments [Not Specified]
3.Primary Outcome
Title Alanine Transaminase (ALT) Levels
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Placebo EPA-E 1800 mg/Day EPA-E 2700 mg/Day
Hide Arm/Group Description:
Placebo: Placebo three times a day (TID) for 365 days
EPA-E: 600 mg TID for 365 days
EPA-E: 900 mg TID for 365 days
Overall Number of Participants Analyzed 55 55 64
Mean (Standard Deviation)
Unit of Measure: U/L
-19.1  (4.79) -9.5  (4.80) -3.0  (4.45)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, EPA-E 1800 mg/Day
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1592
Comments Two-sided p-values testing for significance was performed within treatment group change from baseline and comparisons between treatment groups. Multiple comparison techniques were not applied.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, EPA-E 1800 mg/Day
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 9.6
Confidence Interval (2-Sided) 95%
-3.8 to 23.0
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, EPA-E 2700 mg/Day
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0153
Comments Two-sided p-values testing for significance was performed within treatment group change from baseline and comparisons between treatment groups. Multiple comparison techniques were not applied.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, EPA-E 2700 mg/Day
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 16.0
Confidence Interval (2-Sided) 95%
3.1 to 28.9
Estimation Comments [Not Specified]
Time Frame 1 year
Adverse Event Reporting Description Adverse events solicited at each study visit.
 
Arm/Group Title Placebo EPA-E 1800 mg/Day EPA-E 2700 mg/Day
Hide Arm/Group Description Placebo: Placebo three times a day (TID) for 365 days EPA-E: 600 mg TID for 365 days EPA-E: 900 mg TID for 365 days
All-Cause Mortality
Placebo EPA-E 1800 mg/Day EPA-E 2700 mg/Day
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo EPA-E 1800 mg/Day EPA-E 2700 mg/Day
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/75 (5.33%)   8/82 (9.76%)   5/86 (5.81%) 
Blood and lymphatic system disorders       
Thrombocytopenia  1  1/75 (1.33%)  0/82 (0.00%)  0/86 (0.00%) 
Cardiac disorders       
Angina pectoris  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Gastrointestinal disorders       
Abdominal pain  1  0/75 (0.00%)  2/82 (2.44%)  1/86 (1.16%) 
Pancreatitis  1  0/75 (0.00%)  2/82 (2.44%)  0/86 (0.00%) 
pancreatitis relapsing  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
General disorders       
Non-cardiac chest pain  1  0/75 (0.00%)  2/82 (2.44%)  0/86 (0.00%) 
Asthenia  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Chest pain  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Pyrexia  1  1/75 (1.33%)  0/82 (0.00%)  0/86 (0.00%) 
Infections and infestations       
Appendicitis  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Pneumonia  1  1/75 (1.33%)  0/82 (0.00%)  0/86 (0.00%) 
Post procedural pneumonia  1  0/75 (0.00%)  0/82 (0.00%)  1/86 (1.16%) 
Injury, poisoning and procedural complications       
Post procedural bile leak  1  0/75 (0.00%)  0/82 (0.00%)  1/86 (1.16%) 
Post procedural hematoma  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Investigations       
Electrocardiogram T wave inversion  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Metabolism and nutrition disorders       
Dehydration  1  1/75 (1.33%)  0/82 (0.00%)  0/86 (0.00%) 
Musculoskeletal and connective tissue disorders       
Osteoarthritis  1  0/75 (0.00%)  0/82 (0.00%)  1/86 (1.16%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Carcinoid tumor  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Chronic myelomonocytic leukaemia  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Multiple myeloma  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Nervous system disorders       
Transient ischemic attack  1  0/75 (0.00%)  2/82 (2.44%)  0/86 (0.00%) 
Complicated migraine  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Multiple sclerosis relapse  1  1/75 (1.33%)  0/82 (0.00%)  0/86 (0.00%) 
Syncope  1  1/75 (1.33%)  0/82 (0.00%)  1/86 (1.16%) 
Psychiatric disorders       
Panic attack  1  1/75 (1.33%)  0/82 (0.00%)  0/86 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Hypoxia  1  0/75 (0.00%)  1/82 (1.22%)  1/86 (1.16%) 
Pleural effusion  1  0/75 (0.00%)  1/82 (1.22%)  0/86 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo EPA-E 1800 mg/Day EPA-E 2700 mg/Day
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   71/75 (94.67%)   65/82 (79.27%)   74/86 (86.05%) 
Blood and lymphatic system disorders       
Anaemia  1  4/75 (5.33%)  3/82 (3.66%)  2/86 (2.33%) 
Gastrointestinal disorders       
Nausea  1  7/75 (9.33%)  8/82 (9.76%)  16/86 (18.60%) 
Diarrhoea  1  13/75 (17.33%)  6/82 (7.32%)  11/86 (12.79%) 
Vomiting  1  4/75 (5.33%)  3/82 (3.66%)  10/86 (11.63%) 
Abdominal pain  1  4/75 (5.33%)  5/82 (6.10%)  2/86 (2.33%) 
Abdominal pain upper  1  1/75 (1.33%)  3/82 (3.66%)  6/86 (6.98%) 
Gastroesphageal reflux disease  1  4/75 (5.33%)  2/82 (2.44%)  4/86 (4.65%) 
General disorders       
Fatigue  1  6/75 (8.00%)  3/82 (3.66%)  4/86 (4.65%) 
Oedema peripheral  1  6/75 (8.00%)  3/82 (3.66%)  4/86 (4.65%) 
Pyrexia  1  4/75 (5.33%)  2/82 (2.44%)  3/86 (3.49%) 
Infections and infestations       
Urinary tract infection  1  11/75 (14.67%)  11/82 (13.41%)  8/86 (9.30%) 
Nasopharyngitis  1  9/75 (12.00%)  3/82 (3.66%)  6/86 (6.98%) 
Sinusitis  1  5/75 (6.67%)  4/82 (4.88%)  7/86 (8.14%) 
Gastroenteritis viral  1  3/75 (4.00%)  2/82 (2.44%)  8/86 (9.30%) 
Upper respiratory tract infection  1  3/75 (4.00%)  5/82 (6.10%)  5/86 (5.81%) 
Bronchitis  1  5/75 (6.67%)  1/82 (1.22%)  4/86 (4.65%) 
Diverticulitis  1  4/75 (5.33%)  0/82 (0.00%)  1/86 (1.16%) 
Injury, poisoning and procedural complications       
Procedural pain  1  4/75 (5.33%)  2/82 (2.44%)  1/86 (1.16%) 
Investigations       
Blood creatine phosphokinase increased  1  4/75 (5.33%)  2/82 (2.44%)  0/86 (0.00%) 
Musculoskeletal and connective tissue disorders       
Back pain  1  6/75 (8.00%)  3/82 (3.66%)  5/86 (5.81%) 
Arthralgia  1  0/75 (0.00%)  3/82 (3.66%)  5/86 (5.81%) 
Nervous system disorders       
Dizziness  1  4/75 (5.33%)  4/82 (4.88%)  1/86 (1.16%) 
Psychiatric disorders       
Depression  1  4/75 (5.33%)  4/82 (4.88%)  4/86 (4.65%) 
Vascular disorders       
Hypertension  1  5/75 (6.67%)  4/82 (4.88%)  4/86 (4.65%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Hironori Sato, Director
Organization: Mochida Pharmaceutical Company Ltd.
Phone: +81-3-3225-6331
Responsible Party: Mochida Pharmaceutical Company, Ltd.
ClinicalTrials.gov Identifier: NCT01154985     History of Changes
Other Study ID Numbers: MCH-02-001
First Submitted: June 29, 2010
First Posted: July 1, 2010
Results First Submitted: October 15, 2014
Results First Posted: November 20, 2014
Last Update Posted: November 20, 2014