EVOLVE: Epanova® for Lowering Very High Triglycerides

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01242527
• Collaborator: (none)
• Enrollment: 399
• Locations: 68
• Arms: 4
• Duration (Months): 15
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The primary objective of the study is to determine the efficacy of Epanova (omefas) compared to placebo in lowering serum triglycerides in subjects with severe hypertriglyceridemia.

Condition or Disease	Intervention/Treatment	Phase
Severe Hypertriglyceridemia	Drug: placebo; Drug: omefas; Drug: omefas; Drug: omefas	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 399 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Epanova® (Omefas) in Severe Hypertriglyceridemia
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: placebo	Drug: placebo; 4 capsules (1g) daily for 12 weeks
Experimental: Epanova 2 g	Drug: omefas; 2 capsules (1g) + 2 placebo daily for 12 weeks
Experimental: Epanova 3 g	Drug: omefas; 3 capsules (1g) + 1 placebo daily for 12 weeks
Experimental: Epanova 4 g	Drug: omefas; 4 capsules (1g)daily for 12 weeks

Outcome Measures

Primary Outcome Measures

1. Fasting Serum Triglycerides [12 weeks]

   The primary endpoints are the differences in mean percent changes from baseline to end-of-treatment in triglycerides between placebo and the 2g/day, 3g/day and 4g/day Epanova groups

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men or women, >=18 years of age.

• Very high serum TG values in the range >=500 mg/dL and <2000 mg/dL (>=5.65 mmol/L and <22.60 mmol/L)

Exclusion Criteria:

• Allergy or intolerance to omega-3 fatty acids, omega-3-acid ethyl esters, or fish.

• Known lipoprotein lipase impairment or deficiency or apolipoprotein C-II deficiency or familial dysbetalipoproteinemia.

• Unable to discontinue use of omega-3 drugs/supplements.

• Unable to discontinue use of bile acid sequestrants, fibrates or niacin (other than niacin-containing vitamins <200 mg), or any supplement used to alter lipid metabolism.

• Women who are pregnant, lactating, or planning to become pregnant. Women of childbearing potential who are not using acceptable contraceptive methods.

• Use of tamoxifen, estrogens or progestins that has not been stable for >4 weeks prior to Visit 1.

• Use of oral or injected corticosteroids or anabolic steroids.

• History of pancreatitis.

• History of symptomatic gallstone disease, unless treated with cholecystectomy.

• Uncontrolled diabetes.

• Uncontrolled hypothyroidism or thyroid stimulating hormone (TSH).

• History of cancer (other than basal cell carcinoma) in the past 2 years.

• Cardiovascular event (i.e., myocardial infarction, acute coronary syndrome, new onset angina, stroke, transient ischemic attack, unstable congestive heart failure requiring a change in treatment) or revascularization procedure within six months prior to Visit

• Use of anticoagulants (e.g. warfarin [Coumadin®], coumarin, heparin, enoxaparin, clopidogrel).

• Presence of an aortic aneurysm or resection of an aortic aneurysm within six months prior to Visit 1.

• Recent history (within six months prior to Visit 1) or current significant nephrotic syndrome, pulmonary, hepatic, biliary, gastrointestinal or immunologic disease.

• Poorly controlled hypertension.

• Any of the following laboratory criteria: serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST), glucose, glomerular filtration rate (GFR), platelet count,or hemoglobin outside of study range.

• Recent history (past 12 months) of drug abuse or alcohol abuse.

• Exposure to any investigational product, within 4 weeks prior to Visit 1.

• Presence of any other condition the Investigator believes would interfere with the subject's ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results or put the subject at undue risk

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		National City	California	United States	91950
2		Sacramento	California	United States	95823
3		Manchester	Connecticut	United States	06040
4		Coral Gables	Florida	United States	33134
5		Hialeah	Florida	United States	33012
6		Miami	Florida	United States	33169
7		Ocala	Florida	United States	34471
8		St Petersburg	Florida	United States	33709
9		Summerfield	Florida	United States	34461
10		Atlanta	Georgia	United States	30328
11		Addison	Illinois	United States	60101
12		Chicago	Illinois	United States	60654
13		Louisville	Kentucky	United States	40213
14		Auburn	Maine	United States	04210
15		Olive Branch	Mississippi	United States	38654
16		High Point	North Carolina	United States	27262
17		Salisbury	North Carolina	United States	28144
18		Cincinnati	Ohio	United States	45212
19		Cincinnati	Ohio	United States	45246
20		Columbus	Ohio	United States	43213
21		Oklahoma City	Oklahoma	United States	73103
22		Philadelphia	Pennsylvania	United States	19104
23		Philadelphia	Pennsylvania	United States	19446
24		Bristol	Tennessee	United States	37620
25		Johnson City	Tennessee	United States	37604
26		Kingsport	Tennessee	United States	37660
27		San Antonio	Texas	United States	78215
28		Norfolk	Virginia	United States	23502
29		Richmond	Virginia	United States	23294
30		Olympia	Washington	United States	98502
31		Copenhagen		Denmark	2100
32		Gentofte		Denmark	2820
33		Herlev		Denmark	2730
34		Viborg		Denmark	8800
35		Baja		Hungary	6500
36		Budapest		Hungary	1062
37		Budapest		Hungary	1115
38		Budapest		Hungary	1125
39		Debrecen		Hungary	4032
40		Debrecen		Hungary	4043
41		Satoraljaujhely		Hungary	3980
42		Szekesfehervar		Hungary	8000
43		Szikszo		Hungary	3800
44		Karnal	Haryana	India	132001
45		Bangalore	Karnataka	India	560003
46		Bangalore	Karnataka	India	560054
47		Bangalore	Karnataka	India
48		Banswada	Karnataka	India	560043
49		Indore	Madhya Pradesh	India	452014
50		Pune	Maharashtra	India	411005
51		Jaipur City	Rajasthan	India	302015
52		Chennai	Tamil nadu	India	600010
53		Surat		India	395007
54		Amsterdam		Netherlands	1105AZ
55		Groningen		Netherlands	9711SG
56		Rotterdam		Netherlands	3004BA
57		Rotterdam		Netherlands	3021HC
58		Utrecht		Netherlands	3584CX
59		Moscow		Russian Federation	129090
60		Novosibirsk		Russian Federation	630068
61		St Petersburg		Russian Federation	192288
62		St Petersburg		Russian Federation	196084
63		Kharkiv		Ukraine	61037
64		Kharkiv		Ukraine	61039
65		Kharkiv		Ukraine	61176
66		Kiev		Ukraine	03115
67		Kiev		Ukraine	03680
68		Zaporizhzhya		Ukraine	69118

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Michael H Davidson, MD, FACC, Omthera Pharmaceuticals, Inc

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01242527
• Other Study ID Numbers: OM-EPA-003
• First Posted: Nov 17, 2010
• Last Update Posted: Aug 4, 2016
• Last Verified: Jun 1, 2016

• Keywords provided by AstraZeneca: dyslipidemia; hyperlipidemia; omega-3 carboxylic acid
• Additional relevant MeSH terms: Hypertriglyceridemia

Study Results

Participant Flow

Recruitment Details	The enrollment period started April 2011 and the last subject visit was February 2012. All subjects were qualified at the clinical site and eligibility was determined by each PI (74 US and International clinical sites).
Pre-assignment Detail	Subjects who needed to washout omega-3 drugs/supplements or adjust or add a permitted statin, CAI or combination had an 8-week screening. All other subjects, including those on a stable statin, CAI or statin-CAI, or who needed to washout of bile acid sequestrants, fibrates, niacin and other lipid altering supplements had a 4-week screening period.

Arm/Group Title	Olive Oil (Placebo Control)	Epanova 2 g	Epanova 3 g	Epanova 4 g
Arm/Group Description	placebo : 4 capsules (1g) daily for 12 weeks	omefas : 2 capsules (1g) + 2 placebo daily for 12 weeks	omefas : 3 capsules (1g) + 1 placebo daily for 12 weeks	omefas : 4 capsules (1g)daily for 12 weeks
Period Title: Overall Study
STARTED	99	100	101	99
COMPLETED	94	93	87	90
NOT COMPLETED	5	7	14	9

Baseline Characteristics

Arm/Group Title	Olive Oil (Placebo)	Epanova 2 g	Epanova 3 g	Epanova 4 g	Total
Arm/Group Description	placebo : 4 capsules (1g) daily for 12 weeks	omefas : 2 capsules (1g) + 2 placebo daily for 12 weeks	omefas : 3 capsules (1g) + 1 placebo daily for 12 weeks	omefas : 4 capsules (1g)daily for 12 weeks	Total of all reporting groups
Overall Participants	99	100	101	99	399
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	50.8 (10.59)	51.1 (9.79)	51.2 (8.75)	52.9 (10.92)	51.5 (10.04)
Sex: Female, Male (Count of Participants)
Female	22 22.2%	20 20%	22 21.8%	28 28.3%	92 23.1%
Male	77 77.8%	80 80%	79 78.2%	71 71.7%	307 76.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 6.1%	8 8%	4 4%	7 7.1%	25 6.3%
Not Hispanic or Latino	93 93.9%	92 92%	97 96%	92 92.9%	374 93.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Fasting Serum Triglycerides
Description	The primary endpoints are the differences in mean percent changes from baseline to end-of-treatment in triglycerides between placebo and the 2g/day, 3g/day and 4g/day Epanova groups
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat (ITT) Population was comprised of all subjects who were randomized. In the event that randomized subjects terminated before treatment or had no post-treatment efficacy assessments, a modified ITT Population was implemented.

Arm/Group Title	Olive Oil (Placebo)	Epanova 2 g	Epanova 3 g	Epanova 4 g
Arm/Group Description	placebo : 4 capsules (1g) daily for 12 weeks	omefas : 2 capsules (1g) + 2 placebo daily for 12 weeks	omefas : 3 capsules (1g) + 1 placebo daily for 12 weeks	omefas : 4 capsules (1g)daily for 12 weeks
Measure Participants	98	99	97	99
Least Squares Mean (95% Confidence Interval) [Percent change from baseline]	-4.26	-25.94	-25.46	-30.86

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olive Oil (Placebo), Epanova 2 g
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	P-value adjusted with Dunnett's procedure for multiple comparisons of Epanova vs olive oil
	Method	ANCOVA p-value on ranked data
	Comments	ANCOVA model with baseline value as covariate, and treatment and user/non-user of lipid-altering drugs as factors
Method of Estimation	Estimation Parameter	Placebo adjusted % change from baseline
	Estimated Value	-21.68
	Confidence Interval	(2-Sided) 95%; -40.70 to -2.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	ANCOVA on log-scale TG with baseline value as covariate and treatment and user/non-user of lipid-altering drugs as factors

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olive Oil (Placebo), Epanova 3 g
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	P-value adjusted with Dunnett's procedure for multiple comparisons of Epanova vs olive oil
	Method	ANCOVA p-value on ranked data
	Comments	ANCOVA model with baseline value as covariate, and treatment and user/non-user of lipid-altering drugs as factors
Method of Estimation	Estimation Parameter	Placebo adjusted % change from baseline
	Estimated Value	-21.19
	Confidence Interval	(2-Sided) 95%; -40.32 to -2.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	ANCOVA on log-scale TG with baseline value as covariate, and treatment and user/non-user of lipid-altering drugs as factors

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olive Oil (Placebo), Epanova 4 g
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value adjusted with Dunnett's procedure for multiple comparisons of Epanova vs olive oil
	Method	ANCOVA p-value on ranked data
	Comments	ANCOVA model with baseline value as covariate, and treatment and user/non-user of lipid-altering drugs as factors
Method of Estimation	Estimation Parameter	Placebo adjusted % change from baseline
	Estimated Value	-26.60
	Confidence Interval	(2-Sided) 95%; -45.12 to -8.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	ANCOVA on log-scale TG with baseline value as covariate, and treatment and user/non-user of lipid-altering drugs as factors

Adverse Events

Arm/Group Title	Olive Oil (Placebo)		Epanova 2 g		Epanova 3 g		Epanova 4 g
Arm/Group Description	placebo : 4 capsules (1g) daily for 12 weeks		omefas : 2 capsules (1g) + 2 placebo daily for 12 weeks		omefas : 3 capsules (1g) + 1 placebo daily for 12 weeks		omefas : 4 capsules (1g)daily for 12 weeks
All Cause Mortality
	Olive Oil (Placebo)		Epanova 2 g		Epanova 3 g		Epanova 4 g
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Olive Oil (Placebo)		Epanova 2 g		Epanova 3 g		Epanova 4 g
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/99 (2%)		1/100 (1%)		4/101 (4%)		0/99 (0%)
Cardiac disorders
Myocarditis	1/99 (1%)	1	0/100 (0%)	0	0/101 (0%)	0	0/99 (0%)	0
Angina pectoris	0/99 (0%)	0	1/100 (1%)	1	1/101 (1%)	1	0/99 (0%)	0
Coronary artery disease	0/99 (0%)	0	0/100 (0%)	0	1/101 (1%)	1	0/99 (0%)	0
Implantable defibrillator insertion	0/99 (0%)	0	0/100 (0%)	0	1/101 (1%)	1	0/99 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/99 (1%)	1	0/100 (0%)	0	0/101 (0%)	0	0/99 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/99 (0%)	0	0/100 (0%)	0	1/101 (1%)	1	0/99 (0%)	0
Other (Not Including Serious) Adverse Events
	Olive Oil (Placebo)		Epanova 2 g		Epanova 3 g		Epanova 4 g
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/99 (5.1%)		23/100 (23%)		18/101 (17.8%)		16/99 (16.2%)
Gastrointestinal disorders
Diarrhoea	2/99 (2%)	3	10/100 (10%)	12	6/101 (5.9%)	7	10/99 (10.1%)	11
Nausea	1/99 (1%)	1	6/100 (6%)	9	9/101 (8.9%)	11	5/99 (5.1%)	5
Infections and infestations
Nasopharyngitis	2/99 (2%)	3	7/100 (7%)	7	3/101 (3%)	3	1/99 (1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Individual investigators may publish data arising from their own subjects. The PI will provide the Sponsor with copies of written publications (including abstracts and posters)at least 60 days in advance of submission. Data will be reviewed by all participating investigators prior to publication. The Sponsor will have 60 days to review all definitive publications, such as manuscripts and book chapters, and a minimum of 30 days to review all abstracts.