Severe Hypertriglyceridemia
Conditions
Brief summary
This is a randomized, open-label crossover study. The primary objective of this study is to compare the relative bioavailability of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and the ethyl esters of EPA and DHA in plasma from a single 2 g or 4 g dose of Epanova® or 4 g Lovaza®.
Interventions
DRUGEpanova
DRUGLovaza
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, ≥18 years of age; 2. History of serum TG concentration ≥500 mg/dL within the past 5 years; 3. Have at least one episode of documented hospitalization for pancreatitis due to hypertriglyceridemia in his/her lifetime; 4. Have no health conditions that would prevent him/her from fulfilling the study requirements as judged by the Investigator on the basis of physical examination, ECG, medical history, and routine laboratory test results; 5. Willing to maintain his/her current activity level and to follow either the NCEP TLC diet with a caloric target for weight maintenance or a prescribed low-fat diet during the screening, treatment, and washout periods (Visits 1 through 6b; Weeks -4 through 12); 6. Willing to eat the standardized breakfast, lunch, and dinner meals and snacks before and during Visits 4b and 6b (Weeks 4 and 12); 7. Willing to abstain from alcohol consumption and avoid vigorous physical activity for 48 hours prior to Visits 3 through 6b (Weeks 0 through 12); and 8. Subject understands the study procedures and is willing and able to sign the informed consent form to participate in the study and the Health Insurance Portability and Accountability Act authorization for release of relevant protected health information to the Investigators and study personnel.
Exclusion criteria
1. An allergy or intolerance to omega-3 fatty acids, omega-3-acid ethyl esters, fish, or any of the components of the standardized breakfast, lunch, or dinner meals or snacks (as described to them by study staff) 2. Poorly controlled hypertension (resting blood pressure ≥160 mmHg systolic and/or ≥100 mmHg diastolic) prior to randomization (Visit 3 \[Week 0\]) 3. A history of cancer (other than basal cell carcinoma) in the last 2 years 4. A recent 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), aortic aneurysm or resection, carotid endarterectomy, or revascularization procedure within the 6 months prior to Visit 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline-adjusted AUC0-24 for Plasma Total EPA + Total DHA | participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between. | AUC0-24: Area under the plasma concentration versus time curve, from time 0 to 24 hours after start of the meal |
| Baseline-adjusted Cmax for Plasma Total EPA + Total DHA | participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between. | Cmax: Maximum measured plasma concentration over the time span specified |
Secondary
| Measure | Time frame |
|---|---|
| Baseline-adjusted AUC0-24 for Plasma Total DHA | participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between. |
| Baseline-adjusted Cmax for Plasma Total DHA | This is a crossover study with two treatment periods. The estimated treatment effects were based on the within-subject comparison between the two treatments, each having a 4-week duration and a 4-week wash off period in between. |
| Baseline-adjusted AUC0-24 for Plasma Total EPA | participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between. |
| Baseline-adjusted Cmax for Plasma Total DPA | participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between. |
| Baseline-adjusted AUC0-24 for Plasma Total DPA | participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between. |
| Baseline-adjusted Cmax for Plasma Total EPA | participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between. |
Countries
Canada, United States
Participant flow
Recruitment details
The study subjects were recruited at 6 sites. In total, 30 subjects were screened, of which 15 were randomized to 1 of 4 treatment sequences.
Pre-assignment details
No applicable
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence 1 Epanova 4 g per day:Lovaza 4 g per day | 4 |
| Treatment Sequence 2 Lovaza 4 g per day:Epanova 4 g per day : 4 subjects | 4 |
| Treatment Sequence 3 Epanova 2 g per day:Lovaza 4 g per day | 3 |
| Treatment Sequence 4 Lovaza 4 g per day:Epanova 2 g per day: 4 subjects | 4 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 (Visit 4b, Week 4) | Adverse Event | 0 | 1 | 0 | 0 |
| Period 1 (Visit 4b, Week 4) | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Treatment Sequence 2 | Treatment Sequence 3 | Treatment Sequence 4 | Total | Treatment Sequence 1 |
|---|---|---|---|---|---|
| Age, Continuous | 46.0 years STANDARD_DEVIATION 13.09 | 53.0 years STANDARD_DEVIATION 16.46 | 53.5 years STANDARD_DEVIATION 11.27 | 49.8 years STANDARD_DEVIATION 11.16 | 47.5 years STANDARD_DEVIATION 6.86 |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 0 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 4 Participants | 10 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 3 | 3 / 4 | 5 / 8 | 3 / 4 | 2 / 2 | 1 / 7 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 | 0 / 8 | 0 / 4 | 0 / 2 | 0 / 7 |
Outcome results
Primary
Baseline-adjusted AUC0-24 for Plasma Total EPA + Total DHA
AUC0-24: Area under the plasma concentration versus time curve, from time 0 to 24 hours after start of the meal
Time frame: participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between.
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanova 2 g | Baseline-adjusted AUC0-24 for Plasma Total EPA + Total DHA | 17000 hr*nmol/mL | Geometric Coefficient of Variation 121.7 |
| Epanova 4 g | Baseline-adjusted AUC0-24 for Plasma Total EPA + Total DHA | 18000 hr*nmol/mL | Geometric Coefficient of Variation 104.6 |
| Lovaza 4 g | Baseline-adjusted AUC0-24 for Plasma Total EPA + Total DHA | 12500 hr*nmol/mL | Geometric Coefficient of Variation 80 |
Comparison: In order to address the issue of multiple testing while maintaining overall type I error, a closed testing sequence was used involving 4 analyses stated in the primary objective of this study. In total, 4 statistical tests, each at a significance level of 5%, were carried along the fixed sequence until the first statistically non-significant treatment difference was observed (i.e. p-value\>0.05). This is the first test in the fixed testing sequence.p-value: 0.270295% CI: [64.71, 395.82]Mixed Models Analysis
Comparison: In order to address the issue of multiple testing while maintaining overall type I error, a closed testing sequence was used involving 4 analyses stated in the primary objective of this study. In total, 4 statistical tests, each at a significance level of 5%, were carried along the fixed sequence until the first statistically non-significant treatment difference was observed (i.e. p-value\>0.05). This is the second test in the fixed testing sequence.p-value: 0.636795% CI: [49.17, 300.76]Mixed Models Analysis
Primary
Baseline-adjusted Cmax for Plasma Total EPA + Total DHA
Cmax: Maximum measured plasma concentration over the time span specified
Time frame: participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between.
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanova 2 g | Baseline-adjusted Cmax for Plasma Total EPA + Total DHA | 1090 nmol/mL | Geometric Coefficient of Variation 78.6 |
| Epanova 4 g | Baseline-adjusted Cmax for Plasma Total EPA + Total DHA | 1200 nmol/mL | Geometric Coefficient of Variation 70.2 |
| Lovaza 4 g | Baseline-adjusted Cmax for Plasma Total EPA + Total DHA | 712 nmol/mL | Geometric Coefficient of Variation 76.7 |
Comparison: In order to address the issue of multiple testing while maintaining overall type I error, a closed testing sequence was used involving 4 analyses stated in the primary objective of this study. In total, 4 statistical tests, each at a significance level of 5%, were carried along the fixed sequence until the first statistically non-significant treatment difference was observed (i.e. p-value\>0.05). This is the third test in the fixed testing sequence.p-value: 0.051195% CI: [99.61, 377.47]Mixed Models Analysis
Comparison: In order to address the issue of multiple testing while maintaining overall type I error, a closed testing sequence was used involving 4 analyses stated in the primary objective of this study. In total, 4 statistical tests, each at a significance level of 5%, were carried along the fixed sequence until the first statistically non-significant treatment difference was observed (i.e. p-value\>0.05). This is the fourth test in the fixed testing sequence.p-value: 0.354395% CI: [68.49, 259.52]Mixed Models Analysis
Secondary
Baseline-adjusted AUC0-24 for Plasma Total DHA
Time frame: participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between.
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanova 2 g | Baseline-adjusted AUC0-24 for Plasma Total DHA | 1710 hr*ug/mL | Geometric Coefficient of Variation 136.3 |
| Epanova 4 g | Baseline-adjusted AUC0-24 for Plasma Total DHA | 1550 hr*ug/mL | Geometric Coefficient of Variation 195.2 |
| Lovaza 4 g | Baseline-adjusted AUC0-24 for Plasma Total DHA | 2190 hr*ug/mL | Geometric Coefficient of Variation 86.9 |
p-value: 0.683395% CI: [22.95, 274.45]Mixed Models Analysis
p-value: 0.52295% CI: [20.07, 239.98]Mixed Models Analysis
Secondary
Baseline-adjusted AUC0-24 for Plasma Total DPA
Time frame: participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between.
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanova 2 g | Baseline-adjusted AUC0-24 for Plasma Total DPA | 244 hr*ug/mL | Geometric Coefficient of Variation 225.3 |
| Epanova 4 g | Baseline-adjusted AUC0-24 for Plasma Total DPA | 380 hr*ug/mL | Geometric Coefficient of Variation 240.9 |
| Lovaza 4 g | Baseline-adjusted AUC0-24 for Plasma Total DPA | 108 hr*ug/mL | Geometric Coefficient of Variation 374.3 |
p-value: 0.039195% CI: [112.03, 5071.6]Mixed Models Analysis
p-value: 0.957895% CI: [15.6, 706.33]Mixed Models Analysis
Secondary
Baseline-adjusted AUC0-24 for Plasma Total EPA
Time frame: participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between.
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanova 2 g | Baseline-adjusted AUC0-24 for Plasma Total EPA | 3510 hr*ug/mL | Geometric Coefficient of Variation 117.8 |
| Epanova 4 g | Baseline-adjusted AUC0-24 for Plasma Total EPA | 3930 hr*ug/mL | Geometric Coefficient of Variation 83 |
| Lovaza 4 g | Baseline-adjusted AUC0-24 for Plasma Total EPA | 1730 hr*ug/mL | Geometric Coefficient of Variation 78.4 |
p-value: 0.02195% CI: [119.75, 560.99]Mixed Models Analysis
p-value: 0.125695% CI: [82.22, 385.16]Mixed Models Analysis
Secondary
Baseline-adjusted Cmax for Plasma Total DHA
Time frame: This is a crossover study with two treatment periods. The estimated treatment effects were based on the within-subject comparison between the two treatments, each having a 4-week duration and a 4-week wash off period in between.
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanova 2 g | Baseline-adjusted Cmax for Plasma Total DHA | 116 ug/mL | Geometric Coefficient of Variation 76.1 |
| Epanova 4 g | Baseline-adjusted Cmax for Plasma Total DHA | 118 ug/mL | Geometric Coefficient of Variation 89.2 |
| Lovaza 4 g | Baseline-adjusted Cmax for Plasma Total DHA | 128 ug/mL | Geometric Coefficient of Variation 82.3 |
p-value: 0.903495% CI: [44.92, 244.41]Mixed Models Analysis
p-value: 0.578295% CI: [34.55, 187.95]Mixed Models Analysis
Secondary
Baseline-adjusted Cmax for Plasma Total DPA
Time frame: participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between.
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanova 2 g | Baseline-adjusted Cmax for Plasma Total DPA | 23.0 ug/mL | Geometric Coefficient of Variation 64.2 |
| Epanova 4 g | Baseline-adjusted Cmax for Plasma Total DPA | 26.4 ug/mL | Geometric Coefficient of Variation 83.3 |
| Lovaza 4 g | Baseline-adjusted Cmax for Plasma Total DPA | 11.1 ug/mL | Geometric Coefficient of Variation 128.9 |
p-value: 0.018695% CI: [128.55, 1103.5]Mixed Models Analysis
p-value: 0.595595% CI: [44.97, 386]Mixed Models Analysis
Secondary
Baseline-adjusted Cmax for Plasma Total EPA
Time frame: participants were followed for the duration of study, up to 12 weeks, each treatment having a 4-week duration and a 4-week wash off period in between.
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanova 2 g | Baseline-adjusted Cmax for Plasma Total EPA | 221 ug/mL | Geometric Coefficient of Variation 83 |
| Epanova 4 g | Baseline-adjusted Cmax for Plasma Total EPA | 255 ug/mL | Geometric Coefficient of Variation 65.7 |
| Lovaza 4 g | Baseline-adjusted Cmax for Plasma Total EPA | 100 ug/mL | Geometric Coefficient of Variation 74.9 |
p-value: 0.002595% CI: [164.32, 543.74]Mixed Models Analysis
p-value: 0.041895% CI: [102.95, 340.66]Mixed Models Analysis