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

Study identifier:OM-EPA-004

ClinicalTrials.gov identifier:NCT01408303

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

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

Medical condition

Hypertriglyceridemia

Phase

Phase 3

Healthy volunteers

Study drug

Olive oil, 4g, omega-3-carboxylic acids, 2g, omega-3-carboxylic acids, 4g

Sex

All

Actual Enrollment

646

Study type

Interventional

Age

18 Years +

Date

Study Start Date: 01 Aug 2011

Primary Completion Date: 01 Jun 2012

Study Completion Date: 01 Jun 2012

Study design

Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Nov 2014 by AstraZeneca Pharmaceuticals

Collaborators

Omthera Pharmaceuticals, Inc., Medpac, Inc.

Inclusion and exclusion criteria

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.
11.Use of >750 mL/d grapefruit juice during screening.
12.Known lipoprotein lipase impairment or deficiency, or apolipoprotein C-II deficiency or familial dysbetalipoproteinemia.
13.History of pancreatitis.
14.Type I diabetes mellitus, use of insulin, or HbA1c >10% at Visit 1.
15.Poorly controlled hypertension
16.Uncontrolled hypothyroidism, or thyroid stimulating hormone (TSH) >1.5xULN at Visit 2.
17.Recent history or current significant nephrotic syndrome, pulmonary, hepatic, biliary, gastrointestinal or immunologic disease.
18.History of cancer (except non-melanoma skin cancer, or carcinoma in situ of cervix) within the previous two years.
19.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.
20.Creatine kinase >5.0 times upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times ULN at Visit 2.
21.Current or recent history (past 12 months) of drug or alcohol abuse.
22.Exposure to any investigational agent within 4 weeks prior to Visit 1.
23.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.

Location

Muscle Shoals, Alabama, United States, 35662

Location

Chandler, Arizona, United States, 85224

Location

Phoenix, Arizona, United States, 85020

Location

Little Rock, Arkansas, United States, 72205

Location

Encinitas, California, United States, 92024

Location

Lomita, California, United States, 90717

Location

Los Angeles, California, United States, 90057

Location

Sacramento, California, United States, 95823

Arms	Assigned Interventions
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 Name: 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 Name: 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 Name: omega-3-carboxylic acids

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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 Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
Epanova, 2 g + Statin	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
Epanova, 4 g + 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 + Statin	olive oil, 1 g capsule olive oil: 4 x 1 g capsule daily for 6 weeks prescribed statin

Participant Flow: Overall Study

	Epanova, 2 g + Statin	Epanova, 4 g + Statin	Olive Oil + Statin
STARTED	215	216	216
COMPLETED	209	204	210
NOT COMPLETED	6	12	6
Adverse Event	3	7	2
Lost to Follow-up	0	1	2
Withdrawal by Subject	2	3	1
Protocol Violation	0	1	0
Noncompliance	1	0	1

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

The Baseline Analysis Population comprised the Safety Population defined as subjects who received at least 1 dose of investigational product.

Reporting Groups

	Description
Epanova, 2 g	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
Epanova, 4 g	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	placebo, 1 g capsule placebo : 4 x 1 g capsule daily for 6 weeks

Baseline Measures

	Epanova, 2 g	Epanova, 4 g	Placebo	Total
Number of Participants [units: Participants]	215	216	215	646
Age Categorical [units: participants]
<=18 years	0	0	0	0
Between 18 and 65 years	138	141	124	403
>=65 years	77	75	91	243
Age Continuous [units: years] Mean ± Standard Deviation	60.9 ± 9.95	60.1 ± 9.23	61.5 ± 9.64	60.8 ± 9.61
Gender, Male/Female [units: participants]
Female	92	79	93	264
Male	123	137	122	382
Region of Enrollment [units: participants] United States	215	216	215	646

Outcome Measures

1. Primary Outcome Measure: Serum non-HDL cholesterol [ Time Frame: 6 weeks ]

Measure Type	Primary
Measure Name	Serum non-HDL cholesterol
Measure 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
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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."

Reporting Groups

	Description
Epanova 2 g	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
Epanova 4 g	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	placebo, 1 g capsule placebo : 4 x 1 g capsule daily for 6 weeks

Measured Values

	Epanova 2 g	Epanova 4 g	Placebo
Number of Participants Analyzed [units:participants]	209	207	211
Serum non-HDL cholesterol [units: Percent change from baseline] Least Squares Mean (95% Confidence Interval)	-3.86 (-7.316 to -0.277)	-6.91 (-10.204 to -3.504)	-0.91 (-4.509 to 2.822)

Statistical Analysis 1 for Serum non-HDL cholesterol

Groups^[1]	Epanova 2 g, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.05
Other^[5]	-2.95

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	p-value from ANCOVA with factors for treatment, statin use and potency, and baseline value as a covariate, and adjusted using Hommel’s procedure.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Serum non-HDL cholesterol

Groups^[1]	Epanova 4 g, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-6.00

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	p-value from ANCOVA with factors for treatment, statin use and potency, and baseline value as a covariate, and adjusted using Hommel's procedure.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	No text entered.
Additional 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.

Reporting Groups

	Description
Epanova, 2 g	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
Epanova, 4 g	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	placebo, 1 g capsule placebo : 4 x 1 g capsule daily for 6 weeks

Serious Adverse Events

Epanova, 2 g

Epanova, 4 g

Placebo

Total, serious adverse events

# participants affected / at risk

3/215 (1.40%)

1/216 (0.46%)

3/215 (1.40%)

Musculoskeletal and connective tissue disorders

musculoskeletal chest pain¹,^†

# participants affected / at risk

1/215 (0.47%)

0/216 (0.00%)

0/215 (0.00%)

# events

Gastrointestinal disorders

diverticular perforation²,^†

# participants affected / at risk

1/215 (0.47%)

0/216 (0.00%)

0/215 (0.00%)

# events

Musculoskeletal and connective tissue disorders

osteoarthritis²,^†

# participants affected / at risk

1/215 (0.47%)

0/216 (0.00%)

0/215 (0.00%)

# events

Cardiac disorders

coronary artery disease²,^†

# participants affected / at risk

0/215 (0.00%)

1/216 (0.46%)

0/215 (0.00%)

# events

Infections and infestations

bronchitis²,^†

# participants affected / at risk

0/215 (0.00%)

0/216 (0.00%)

1/215 (0.47%)

# events

Gastrointestinal disorders

intestinal obstruction¹,^†

# participants affected / at risk

0/215 (0.00%)

0/216 (0.00%)

1/215 (0.47%)

# events

Metabolism and nutrition disorders

hyperglycemia²,^†

# participants affected / at risk

0/215 (0.00%)

0/216 (0.00%)

1/215 (0.47%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (version 14.1
2	Term from vocabulary, MedDRA (version14.1)
3	Term from vocabulary, MedDRA 14.1

Other Adverse Events

Time Frame	No text entered.
Additional 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.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Epanova, 2 g	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
Epanova, 4 g	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	placebo, 1 g capsule placebo : 4 x 1 g capsule daily for 6 weeks

Other Adverse Events

Epanova, 2 g

Epanova, 4 g

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

13/215 (6.05%)

36/216 (16.67%)

5/215 (2.33%)

Gastrointestinal disorders

Diarrhea¹,^†

# participants affected / at risk

13/215 (6.05%)

36/216 (16.67%)

5/215 (2.33%)

# events

Gastrointestinal disorders

Nausea²,^†

# participants affected / at risk

6/215 (2.79%)

13/216 (6.02%)

3/215 (1.40%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (version14.1)
2	Term from vocabulary, MedDRA (v. 14.1)
3	Term from vocabulary, MedDRA 14.1

Certain Agreements

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

There IS 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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Torbjörn Lundström
Organization:	AstraZeneca Pharmaceuticals
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Michael H Davidson

Omthera Pharmaceuticals, Inc

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Trial Results Summaries