Epanova® Compared to Lovaza® In a Pharmacokinetic, Single-dose, Evaluation - ECLIPSE

Study identifier:OM-EPA-001

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Randomized, Open-label, Four-Way Crossover Study to Compare the Relative Bioavailability of a Single Dose of Epanova® With Lovaza® After a Low-Fat and High-Fat Meal

Medical condition

severe hypertriglyceridemia

Phase

Phase 2

Healthy volunteers

Yes

Study drug

Epanova (4 g) and Lovaza (4 g), Lovaza (4 g) and Epanova (4 g)

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years +

Date

Study Start Date: 01 Sept 2010

Primary Completion Date: 01 Nov 2010

Study Completion Date: 01 Nov 2010

Study design

Allocation: Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Jun 2015 by AstraZeneca Pharmaceuticals

Collaborators

Radiant Research

Inclusion and exclusion criteria

Location

Radiant Research

Chicago, Illinois, United States, 60654

Arms	Assigned Interventions
Active Comparator: Epanova-Lovaza-Epanova-Lovaza	Drug: Epanova (4 g) and Lovaza (4 g) Single dose of Epanova (omefas), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Epanova (omefas), 4x1g capsules, taken with high-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters, 4x1g capsules, taken with high-fat meals Other Name: Note that omefas corresponds to omega-3 carboxylic acids
Active Comparator: Lovaza-Epanova-Lovaza-Epanova	Drug: Lovaza (4 g) and Epanova (4 g) Single dose of Lovaza (omega-3-acid ethyl esters), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Epanova (omefas), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters,4x1g capsules, taken with high-fat meals, 7 day washout followed by single dose ofEpanova (omefas),4x1g capsules, taken with high-fat meals Other Name: Note that omefas corresponds to omega-3 carboxylic acids

Arms

Assigned Interventions

Active Comparator: Epanova-Lovaza-Epanova-Lovaza

Drug: Epanova (4 g) and Lovaza (4 g)
Single dose of Epanova (omefas), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Epanova (omefas), 4x1g capsules, taken with high-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters, 4x1g capsules, taken with high-fat meals

Other Name: Note that omefas corresponds to omega-3 carboxylic acids

Active Comparator: Lovaza-Epanova-Lovaza-Epanova

Drug: Lovaza (4 g) and Epanova (4 g)
Single dose of Lovaza (omega-3-acid ethyl esters), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Epanova (omefas), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters,4x1g capsules, taken with high-fat meals, 7 day washout followed by single dose ofEpanova (omefas),4x1g capsules, taken with high-fat meals

Other Name: Note that omefas corresponds to 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 October 2010 and the last subject visit was November 2010. All subjects were qualified at the clinical site and eligibility was determined by the PI (one US clinical site).

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
This was a 4-way crossover study with a minimum 7-day washout period between each treatment. Subjects were healthy volunteers aged ≥ 18 with a body mass index 25-35 kg/m2 and who were not intolerant to omega-3 products or fish. Subjects were instructed to follow the TLC diet and abstain from omega-3 products or fish for screening and all periods.

Reporting Groups

	Description
Epanova-Lovaza-Epanova-Lovaza	Epanova (4 g) and Lovaza (4 g) : Single dose of Epanova (omefas; corresponds to omega-3 carboxylic acids), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Epanova (omefas), 4x1g capsules, taken with high-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters, 4x1g capsules, taken with high-fat meals
Lovaza-Epanova-Lovaza-Epanova	Lovaza (4 g) and Epanova (4 g) : Single dose of Lovaza (omega-3-acid ethyl esters), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Epanova (omefas; corresponds to omega-3 carboxylic acids), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters,4x1g capsules, taken with high-fat meals, 7 day washout followed by single dose of Epanova (omefas),4x1g capsules, taken with high-fat meals

Description

Epanova-Lovaza-Epanova-Lovaza

Epanova (4 g) and Lovaza (4 g) : Single dose of Epanova (omefas; corresponds to omega-3 carboxylic acids), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Epanova (omefas), 4x1g capsules, taken with high-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters, 4x1g capsules, taken with high-fat meals

Lovaza-Epanova-Lovaza-Epanova

Lovaza (4 g) and Epanova (4 g) : Single dose of Lovaza (omega-3-acid ethyl esters), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Epanova (omefas; corresponds to omega-3 carboxylic acids), 4x1g capsules, taken with low-fat meals, 7 day washout followed by single dose of Lovaza (omega-3-acid ethyl esters,4x1g capsules, taken with high-fat meals, 7 day washout followed by single dose of Epanova (omefas),4x1g capsules, taken with high-fat meals

Participant Flow for 4 periods

Period 1: Low-Fat Period I

	Epanova-Lovaza-Epanova-Lovaza	Lovaza-Epanova-Lovaza-Epanova
STARTED	27	27
COMPLETED	27	27
NOT COMPLETED	0	0

Period 2: Low-Fat Period II

	Epanova-Lovaza-Epanova-Lovaza	Lovaza-Epanova-Lovaza-Epanova
STARTED	26	27
COMPLETED	26	27
NOT COMPLETED	0	0

Period 3: High-Fat Period III

	Epanova-Lovaza-Epanova-Lovaza	Lovaza-Epanova-Lovaza-Epanova
STARTED	26	26
COMPLETED	25	26
NOT COMPLETED	1	0
Protocol Violation	1	0

Period 4: High-Fat Period IV

	Epanova-Lovaza-Epanova-Lovaza	Lovaza-Epanova-Lovaza-Epanova
STARTED	25	26
COMPLETED	25	26
NOT COMPLETED	0	0

Baseline Characteristics

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

To be included in the baseline analysis, subjects had to receive at least one dose of investigational product; all randomized subjects (n = 54) were included in the baseline analysis.

Reporting Groups

	Description
All Subjects	All subjects received both Epanova (E) and Lovaza (L), and both under fasted and fed conditions. Subjects were randomized 1:1 to one of the following treatment period sequences: ELEL or LELE.

Baseline Measures

	All Subjects
Number of Participants [units: Participants]	54
Age Continuous [units: years] Mean ± Standard Deviation	44.6 ± 11.96
Gender, Male/Female [units: participants]
Female	13
Male	41
Ethnicity (NIH/OMB) [units: participants]
Hispanic or Latino	9
Not Hispanic or Latino	45
Unknown or Not Reported	0
Region of Enrollment [units: participants] United States	54

Outcome Measures

1. Primary Outcome Measure: AUC(0-t): Area Under the plasma concentration-time Curve from 0 to 24 hours (the final time with a concentration ≥ LOQ) [ Time Frame: Blood samples were obtained pre-dose at -1.0, -0.5, and 0 hours and after dose administration at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours. ]

Measure Type	Primary
Measure Name	AUC(0-t): Area Under the plasma concentration-time Curve from 0 to 24 hours (the final time with a concentration ≥ LOQ)
Measure Description	Analyses of the outcome measures presented are for baseline-adjusted data for total (esterified and unesterfied) EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation.
Time Frame	Blood samples were obtained pre-dose at -1.0, -0.5, and 0 hours and after dose administration at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours.
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.

Reporting Groups

	Description
Epanova (Low-Fat Period)	Single dose of Epanova (omefas), 4*1g capsules, taken after fasting 12 hours with no breakfast, followed with no-fat lunch and low-fat dinner
Lovaza (Low-Fat Period)	Single dose of Lovaza (omega-3-acid ethyl esters), 4*1g capsules, taken after fasting 12 hours with no breakfast, followed with no-fat lunch and low-fat dinner

Measured Values

	Epanova (Low-Fat Period)	Lovaza (Low-Fat Period)
Number of Participants Analyzed [units:participants]	51	51
AUC(0-t): Area Under the plasma concentration-time Curve from 0 to 24 hours (the final time with a concentration ≥ LOQ) [units: nmol.h/mL] Geometric Mean (Full Range)	2650.1612 (689.2702 to 7883.4790)	661.9490 (-603.7871 to 2967.3160)

Statistical Analysis 1 for AUC(0-t): Area Under the plasma concentration-time Curve from 0 to 24 hours (the final time with a concentration ≥ LOQ)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	<0.001
Other^[5]	400.36
90% Confidence Interval	( 326.87 to 490.36 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Results for the analyses of the High-Fat Periods were not posted because the critical comparison was the response of Lovaza versus Epanova to the clinically relevant low-fat diet to be used as adjunct in hypertriglyceridemia.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	ANOVA on log-trans baseline-adj PK values using sequence, period, and treatments as fixed effects and subject nested within sequence as random effect
[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.

2. Primary Outcome Measure: AUC(inf): Area Under the plasma concentration-time Curve from 0 to infinity [ Time Frame: Blood samples were obtained pre-dose at -1.0, -0.5, and 0 hours and after dose administration at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours. ]

Measure Type	Primary
Measure Name	AUC(inf): Area Under the plasma concentration-time Curve from 0 to infinity
Measure Description	Analyses of the outcome measures presented are for baseline-adjusted data for total (esterified and unesterfied) EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation.
Time Frame	Blood samples were obtained pre-dose at -1.0, -0.5, and 0 hours and after dose administration at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours.
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.

Reporting Groups

	Description
Epanova (Low-Fat Period)	Single dose of Epanova (omefas), 4*1g capsules, taken after fasting 12 hours with no breakfast, followed with no-fat lunch and low-fat dinner
Lovaza (Low-Fat Period)	Single dose of Lovaza (omega-3-acid ethyl esters), 4*1g capsules, taken after fasting 12 hours with no breakfast, followed with no-fat lunch and low-fat dinner

Measured Values

	Epanova (Low-Fat Period)	Lovaza (Low-Fat Period)
Number of Participants Analyzed [units:participants]	51	51
AUC(inf): Area Under the plasma concentration-time Curve from 0 to infinity [units: nmol.h/mL] Geometric Mean (Full Range)	5219.56 (1388.8324 to 13802.1423)	803.42 (217.7803 to 2810.6873)

Statistical Analysis 1 for AUC(inf): Area Under the plasma concentration-time Curve from 0 to infinity

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	<0.01
Other^[5]	649.66
90% Confidence Interval	( 511.75 to 824.75 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Results for the analyses of the High-Fat Periods were not posted because the critical comparison was the response of Lovaza versus Epanova to the clinically relevant low-fat diet to be used as adjunct in hypertriglyceridemia.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	ANOVA model with baseline value as covariate, and treatment and user/non-user of lipid-altering drugs as factors. LSM estimate performed on log-scale
[5]	Other relevant estimation information:
	No text entered.

3. Primary Outcome Measure: C(max): Maximum plasma concentration [ Time Frame: Blood samples were obtained pre-dose at -1.0, -0.5, and 0 hours and after dose administration at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours. ]

Measure Type	Primary
Measure Name	C(max): Maximum plasma concentration
Measure Description	Analyses of the outcome measures presented are for baseline-adjusted data for total (esterified and unesterfied) EPA and DHA since the presence of endogenous levels of these fatty acids would likely contribute to intra-subject variability and affect the analyses and interpretation.
Time Frame	Blood samples were obtained pre-dose at -1.0, -0.5, and 0 hours and after dose administration at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours.
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.

Reporting Groups

	Description
Epanova (Low-Fat Period)	Single dose of Epanova (omefas), 4*1g capsules, taken after fasting 12 hours with no breakfast, followed with no-fat lunch and low-fat dinner
Lovaza (Low-Fat Period)	Single dose of Lovaza (omega-3-acid ethyl esters), 4*1g capsules, taken after fasting 12 hours with no breakfast, followed with no-fat lunch and low-fat dinner

Measured Values

	Epanova (Low-Fat Period)	Lovaza (Low-Fat Period)
Number of Participants Analyzed [units:participants]	51	51
C(max): Maximum plasma concentration [units: nmol/mL] Geometric Mean (Full Range)	225.7920 (38.7545 to 754.0992)	61.0818 (21.0820 to 843.7832)

Statistical Analysis 1 for C(max): Maximum plasma concentration

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	<0.001
Other^[5]	369.66
90% Confidence Interval	( 301.74 to 452.86 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Results for the analyses of the High-Fat Periods were not posted because the critical comparison was the response of Lovaza versus Epanova to the clinically relevant low-fat diet to be used as adjunct in hypertriglyceridemia.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[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	The adverse event safety results were grouped and analyzed for the entire population since the OM-3 FFA and OM-3 EE treatments were single-dose administrations received by all subjects and the protocol was not developed as an exposure-response study design.

Reporting Groups

	Description
All Subjects	All subjects received both Epanova (E) and Lovaza (L), and both under fasted and fed conditions. Subjects were randomized 1:1 to one of the following treatment period sequences: ELEL or LELE.

Serious Adverse Events

	All Subjects
Total, serious adverse events
# participants affected / at risk	0/54 (0.00%)

Other Adverse Events

Time Frame	No text entered.
Additional Description	The adverse event safety results were grouped and analyzed for the entire population since the OM-3 FFA and OM-3 EE treatments were single-dose administrations received by all subjects and the protocol was not developed as an exposure-response study design.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
All Subjects	All subjects received both Epanova (E) and Lovaza (L), and both under fasted and fed conditions. Subjects were randomized 1:1 to one of the following treatment period sequences: ELEL or LELE.