ESPRIT: [E]PANOVA Combined With a [S]TATIN in [P]ATIENTS With HYPERT[R]IGLYCER[I]DEMIA to Reduce Non-HDL CHOLES[T]EROL

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01408303
• Collaborator: Omthera Pharmaceuticals, Inc (Industry), Medpace, Inc. (Industry)
• Enrollment: 646
• Locations: 90
• Arms: 3
• Duration (Months): 10
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The primary objective is to evaluate the efficacy of adding Epanova (2 g or 4 g daily) to an optimal statin monotherapy for lowering non-high-density lipoprotein (non-HDL) cholesterol in subjects with persistent hypertriglyceridemia and high risk for cardiovascular disease.

Condition or Disease	Intervention/Treatment	Phase
Hypertriglyceridemia; Cardiovascular Disease	Drug: Olive oil, 4g; Drug: omega-3-carboxylic acids, 2g; Drug: omega-3-carboxylic acids, 4g	Phase 3

Detailed Description

The primary efficacy variable is serum non-HDL cholesterol. The primary endpoints are the differences in mean percent changes from baseline to end-of-treatment in non-HDL cholesterol between placebo and the 2g/day and 4g/day Epanova groups. Baseline is defined as the average of Visits 2, 3 and 4 (Weeks -2, -1 and 0) and end-of-treatment is the average of Visits 5 and 6 (Weeks 5 and 6).

Study Design

• Study Type: Interventional
• Actual Enrollment: 646 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 6-Week, Randomized, Double-Blind, Placebo(Olive Oil)-Controlled Study to Assess the Efficacy and Safety of Add-On Epanova® to Statin Therapy in Subjects With Persistent Hypertriglyceridemia and High Risk for Cardiovascular Disease
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Olive Oil olive oil: 4 g/day + prescription statin	Drug: Olive oil, 4g; Olive oil: 4 x 1 g capsule daily for 6 weeks + prescription statin; Other Names: Placebo comparator
Experimental: Epanova, 2 g omega-3-carboxylic acids, 2g/day + prescription statin	Drug: omega-3-carboxylic acids, 2g; Epanova: 2 x 1 g capsule + olive oil 2 x 1 g capsule daily for 6 weeks + prescription statin; Other Names: omega-3-carboxylic acids
Experimental: Epanova, 4 g omega-3-carboxylic acids, 4g/day + prescription statin	Drug: omega-3-carboxylic acids, 4g; Epanova: 4 x 1 g capsule daily for 6 weeks + prescription statin; Other Names: omega-3-carboxylic acids

Outcome Measures

Primary Outcome Measures

1. Serum Non-HDL Cholesterol [6 weeks]

   The primary endpoints are the differences in mean percent changes from baseline to end-of-treatment in non-HDL cholesterol between placebo and the 2g/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:

1. Men or women, ≥18 years of age.

2. Fasting triglyceride (TG) level ≥200 mg/dL and <500 mg/dL.

3. The subject is a high risk for a future cardiovascular event.

4. The subject is treated with a statin and at or near LDL-C goal.

Exclusion Criteria:

1. Allergy or intolerance to omega-3 fatty acids and omega-3-acid ethyl esters.

2. Use of fibrates, bile acid sequestrants, or niacin or its analogues (greater than 200 mg/d) during screening.

3. Use of simvastatin 80 mg or Vytorin10/80 mg during screening.

4. Use of any eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) products.

5. Use of any supplement for the purpose of lowering plasma cholesterol during screening.

6. Use of weight loss drugs or programs during screening.

7. Use of erythromycin, telithromycin, clarithromycin, cyclosporine, itraconazole, ketoconazole, protease inhibitors, or nefazodone during screening.

8. Use of anticoagulants during screening.

9. Use of oral or injected corticosteroids during screening.

10. Use of tamoxifen, estrogens, progestins, or testosterone, that has not been stable for

4 weeks at Visit 1, or is unstable during screening.

1. Use of >750 mL/d grapefruit juice during screening.

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

3. History of pancreatitis.

4. Type I diabetes mellitus, use of insulin, or HbA1c >10% at Visit 1.

5. Poorly controlled hypertension

6. Uncontrolled hypothyroidism, or thyroid stimulating hormone (TSH) >1.5xULN at Visit 2.

7. Recent history or current significant nephrotic syndrome, pulmonary, hepatic, biliary, gastrointestinal or immunologic disease.

8. History of cancer (except non-melanoma skin cancer, or carcinoma in situ of cervix) within the previous two years.

9. Females who are pregnant, planning to be pregnant during the study period, lactating, or women of childbearing potential who are not using an acceptable method of contraception.

10. Creatine kinase >5.0 times upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times ULN at Visit 2.

11. Current or recent history (past 12 months) of drug or alcohol abuse.

12. Exposure to any investigational agent within 4 weeks prior to Visit 1.

13. 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		Muscle Shoals	Alabama	United States	35662
2		Chandler	Arizona	United States	85224
3		Phoenix	Arizona	United States	85020
4		Little Rock	Arkansas	United States	72205
5		Encinitas	California	United States	92024
6		Lomita	California	United States	90717
7		Los Angeles	California	United States	90057
8		Sacramento	California	United States	95823
9		San Diego	California	United States	92117
10		Spring Valley	California	United States	91978
11		Westlake Village	California	United States	91361
12		Colorado Springs	Colorado	United States	80902
13		Denver	Colorado	United States	80239
14		Brandon	Florida	United States	33511
15		Clearwater	Florida	United States	33756
16		Coral Gables	Florida	United States	33134
17		Hialeah	Florida	United States	33012
18		Jacksonville	Florida	United States	32205
19		Jacksonville	Florida	United States	32223
20		Jupiter	Florida	United States	33458
21		Melbourne	Florida	United States	32901
22		Miami	Florida	United States	33014
23		Miami	Florida	United States	33169
24		Miami	Florida	United States	33183
25		New Port Richey	Florida	United States	34652
26		Ocala	Florida	United States	34471
27		Orlando	Florida	United States	32806
28		Oviedo	Florida	United States	32765
29		Ponte Vedra	Florida	United States	32081
30		St. Petersburg	Florida	United States	33709
31		Addison	Illinois	United States	60101
32		Chicago	Illinois	United States	60654
33		Oakbrook Terrace	Illinois	United States	60181
34		Indianapolis	Indiana	United States	46260
35		Newton	Kansas	United States	67114
36		Wichita	Kansas	United States	67205
37		Wichita	Kansas	United States	67207
38		Louisville	Kentucky	United States	40213
39		Madisonville	Kentucky	United States	42431
40		Auburn	Maine	United States	04210
41		Oxon Hill	Maryland	United States	20745
42		Troy	Michigan	United States	48098
43		Edina	Minnesota	United States	55435
44		Chesterfield	Missouri	United States	63017
45		Kansas City	Missouri	United States	64111
46		St. Louis	Missouri	United States	63128
47		Butte	Montana	United States	59701
48		Las Vegas	Nevada	United States	89123
49		Berlin	New Jersey	United States	08009
50		Endwell	New York	United States	13760
51		New Windsor	New York	United States	12553
52		Rochester	New York	United States	14609
53		Cary	North Carolina	United States	27518
54		Charlotte	North Carolina	United States	28602
55		Hickory	North Carolina	United States	28602
56		High Point	North Carolina	United States	27265
57		Raleigh	North Carolina	United States	27527
58		Raleigh	North Carolina	United States	27612
59		Salisbury	North Carolina	United States	28144
60		Statesville	North Carolina	United States	28677
61		Winston-Salem	North Carolina	United States	27103
62		Cincinnati	Ohio	United States	45212
63		Cincinnati	Ohio	United States	45219
64		Cincinnati	Ohio	United States	45242
65		Cincinnati	Ohio	United States	45246
66		Columbus	Ohio	United States	43213
67		Lyndhurst	Ohio	United States	44124
68		Marion	Ohio	United States	43302
69		Oklahoma City	Oklahoma	United States	73112
70		Tulsa	Oklahoma	United States	74136
71		Eugene	Oregon	United States	97404
72		Harleysville	Pennsylvania	United States	19438
73		Jersey Shore	Pennsylvania	United States	17740
74		Lansdale	Pennsylvania	United States	19446
75		Philadelphia	Pennsylvania	United States	19104
76		Mount Pleasant	South Carolina	United States	29464
77		Mt Pleasant	South Carolina	United States	29464
78		Rapid City	South Dakota	United States	57702
79		Bristol	Tennessee	United States	37620
80		Gray	Tennessee	United States	37615
81		Kingsport	Tennessee	United States	37660
82		Corpus Christi	Texas	United States	78404
83		Houston	Texas	United States	77074
84		Katy	Texas	United States	77450
85		San Antonio	Texas	United States	78205
86		Murray	Utah	United States	84123
87		Salt Lake City	Utah	United States	84107
88		Norfolk	Virginia	United States	23502
89		Richmond	Virginia	United States	23294
90		Olympia	Washington	United States	98502

Sponsors and Collaborators

• AstraZeneca
• Omthera Pharmaceuticals, Inc
• Medpace, Inc.

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: NCT01408303
• Other Study ID Numbers: OM-EPA-004; OM-EPA-004
• First Posted: Aug 3, 2011
• Last Update Posted: Dec 5, 2014
• Last Verified: Nov 1, 2014

• Keywords provided by AstraZeneca: dyslipidemia; hyperlipidemia; cardiovascular risk
• Additional relevant MeSH terms: Cardiovascular Diseases; Hypertriglyceridemia

Study Results

Participant Flow

Recruitment Details	The enrollment period started August 2011 and the last subject visit was May 2012. All subjects were qualified at the clinical site and eligibility was determined by each PI (96 sites)
Pre-assignment Detail	Subjects underwent 6-week washout and diet stabilization period, discontinued use of any non-statin lipid therapies, continued their current statin regimen, and followed the NCEP TLC diet. Men and women considered to be at high risk for atherosclerotic CVD and who had high serum TG (≥200 mg/dL and <500 mg/dL) were eligible for randomization.

Arm/Group Title	Epanova, 2 g + Statin	Epanova, 4 g + Statin	Olive Oil + Statin
Arm/Group Description	omega-3 carboxylic acids, 1 g capsule omega-3 carboxylic acids + olive oil: omega-3 carboxylic acids 2 x 1 g capsule + olive oil 2 x 1 g capsule daily for 6 weeks prescribe statin	omega-3 carboxylic acids, 1 g capsule omega-3 carboxylic acids: omega-3 carboxylic acids 4 x 1 g capsule daily for 6 weeks prescribed statin	olive oil, 1 g capsule olive oil: 4 x 1 g capsule daily for 6 weeks prescribed statin
Period Title: Overall Study
STARTED	215	216	216
COMPLETED	209	204	210
NOT COMPLETED	6	12	6

Baseline Characteristics

Arm/Group Title	Epanova, 2 g	Epanova, 4 g	Placebo	Total
Arm/Group Description	omega-3-carboxylic acids, 1 g capsule omega-3-carboxylic acids + placebo : omega-3-carboxylic acids 2 x 1 g capsule + placebo 2 x 1 g capsule daily for 6 weeks	omega-3-carboxylic acids, 1 g capsule omega-3-carboxylic acids: omega-3-carboxylic acids 4 x 1 g capsule daily for 6 weeks	placebo, 1 g capsule placebo : 4 x 1 g capsule daily for 6 weeks	Total of all reporting groups
Overall Participants	215	216	215	646
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	138 64.2%	141 65.3%	124 57.7%	403 62.4%
>=65 years	77 35.8%	75 34.7%	91 42.3%	243 37.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.9 (9.95)	60.1 (9.23)	61.5 (9.64)	60.8 (9.61)
Sex: Female, Male (Count of Participants)
Female	92 42.8%	79 36.6%	93 43.3%	264 40.9%
Male	123 57.2%	137 63.4%	122 56.7%	382 59.1%
Region of Enrollment (participants) [Number]
United States	215 100%	216 100%	215 100%	646 100%

Outcome Measures

1. Primary Outcome

Title	Serum Non-HDL Cholesterol
Description	The primary endpoints are the differences in mean percent changes from baseline to end-of-treatment in non-HDL cholesterol between placebo and the 2g/day and 4g/day Epanova groups.
Time Frame	6 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	Epanova 2 g	Epanova 4 g	Placebo
Arm/Group Description	omega-3-carboxylic acids, 1 g capsule omega-3-carboxylic acids + placebo: omega-3-carboxylic acids 2 x 1 g capsule + placebo 2 x 1 g capsule daily for 6 weeks	omega-3-carboxylic acids, 1 g capsule omega-3-carboxylic acids: omega-3-carboxylic acids 4 x 1 g capsule daily for 6 weeks	placebo, 1 g capsule placebo : 4 x 1 g capsule daily for 6 weeks
Measure Participants	209	207	211
Least Squares Mean (95% Confidence Interval) [Percent change from baseline]	-3.86	-6.91	-0.91

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Epanova 2 g, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments	p-value from ANCOVA with factors for treatment, statin use and potency, and baseline value as a covariate, and adjusted using Hommel's procedure.
Method of Estimation	Estimation Parameter	LS mean difference relative to olive oil
	Estimated Value	-2.95
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Epanova 4 g, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	p-value from ANCOVA with factors for treatment, statin use and potency, and baseline value as a covariate, and adjusted using Hommel's procedure.
Method of Estimation	Estimation Parameter	LS mean difference relative to olive oil
	Estimated Value	-6.00
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Adverse Event Reporting Description	A total of 78 (12.1%) adverse events (AEs) were considered related to treatment: 13 in placebo, 21 in Epanova 2 g and 44 in Epanova 4 g. Twelve subjects (1.9%) had AEs causing discontinuation: 2 in placebo, 3 in Epanova 2 g and 7 in Epanova 4 g. Gastrointestinal disorders had the highest occurrence but most were mild or moderate and self-limiting.
Arm/Group Title	Epanova, 2 g		Epanova, 4 g		Placebo
Arm/Group Description	omega-3-carboxylic acids, 1 g capsule omega-3-carboxylic acids + placebo : omega-3-carboxylic acids 2 x 1 g capsule + placebo 2 x 1 g capsule daily for 6 weeks		omega-3-carboxylic acids, 1 g capsule omega-3-carboxylic acids: omega-3-carboxylic acids 4 x 1 g capsule daily for 6 weeks		placebo, 1 g capsule placebo : 4 x 1 g capsule daily for 6 weeks
All Cause Mortality
	Epanova, 2 g		Epanova, 4 g		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Epanova, 2 g		Epanova, 4 g		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/215 (1.4%)		1/216 (0.5%)		3/215 (1.4%)
Cardiac disorders
coronary artery disease	0/215 (0%)	0	1/216 (0.5%)	1	0/215 (0%)	0
Gastrointestinal disorders
diverticular perforation	1/215 (0.5%)	1	0/216 (0%)	0	0/215 (0%)	0
intestinal obstruction	0/215 (0%)	0	0/216 (0%)	0	1/215 (0.5%)	1
Infections and infestations
bronchitis	0/215 (0%)	0	0/216 (0%)	0	1/215 (0.5%)	1
Metabolism and nutrition disorders
hyperglycemia	0/215 (0%)	0	0/216 (0%)	0	1/215 (0.5%)	1
Musculoskeletal and connective tissue disorders
musculoskeletal chest pain	1/215 (0.5%)	1	0/216 (0%)	0	0/215 (0%)	0
osteoarthritis	1/215 (0.5%)	1	0/216 (0%)	0	0/215 (0%)	0
Other (Not Including Serious) Adverse Events
	Epanova, 2 g		Epanova, 4 g		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/215 (6%)		36/216 (16.7%)		5/215 (2.3%)
Gastrointestinal disorders
Diarrhea	13/215 (6%)	13	36/216 (16.7%)	36	5/215 (2.3%)	5
Nausea	6/215 (2.8%)	6	13/216 (6%)	13	3/215 (1.4%)	3

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.