• Male or female patients between the ages of 18-75 years
• Serum TG > 5.65 mmol/L and < 22.6 mmol/L

• TG > 22.6 mmol/L (high risk for development of acute pancreatitis and referred for treatment)
• Consumption of cold-water fish > 1 time per week
• Type III hyperlipidemia
• Myocardial infarction < 6 months before entering study
• Serum alanine aminogransferase > three times the upper normal value
• Fasting serum glucose > 200 mg/dl
• Serum creatinine > 2 mg/dl
• Platelet counts < 60 x 10⁹/L
• Hemoglobin < 10 g/dl
•  Presence of any clinically significant disease (as judged by the investigators)
• Excessive use of alcohol (< two drinks/day)
• Drug abuse
• Any condition associated with a risk of poor compliance
• If female, could not be pregnant or breastfeeding
• If taking gemfibrozil, were required to discontinue the drug > 6 weeks before entering the study dietary phase
• If consuming omego-3 fatty acid-containing products such as cod liver oil, required to discontinue > 4 weeks before beginning the study
• If consuming lipid decreasing fibers, required to discontinue 4 233ks before beginnning study

Recruitment Not discussed

Design Prospective, randomized doubled-blind, parallel study

Blinding used (if applicable) Not discussed

Intervention (if applicable)

• All subjects received instruction in the National Cholesterol Education Program Step I diet by the hospital dietitian before beginning the dietary phase
  • Subjects were urged to maintain a stable lifestyle, including diet, exercise, smoking and alcohol consumption throughout the trial Dietary run in phase x 4 weeks
• Dietary run in phase x 4 weeks
• Serum TG were measured four times, 1 week apart (weeks -4, -2, -1 and 0 (because the TG concentration is known to fluctuate considerably in persons with hypertriglyceridemia) during the run-in phase
  • The mean of weeks -2 and -1 was  used for purposes of qualification to enter the study
  • The mean of weeks -2, -1 and 0 for aseline balues was used in subsequent data analysis
• Randomized to Omacor or placebo for 16 weeks
  • Omacor (85% omega-3 fatty acid ethyl esters)
    • Contains 3.4 g Eicosapentonoic acid (EPA) + docosahexanoic acid (DHA) + 18 mg vitamin E per day
  • Placebo (corn oil)
• Other visits took place at 4, 8, and 12 weeks after the subjects had been assigned to groups.

Statistical Analysis

• Results are expressed as means ± SD
• For all parameters except TG, comparisons within groups were analyzed by the Student's t test for paired samples.
• For comparisons of the changes from baseleine to endoint between groups were analyzed by the two-sample t-test.
• Because TG were not normally distributed in these subjects, the Wilcoxon signed rank test was used within groups and the Mann-Whitney rank sum test between groups.
• Parametric analyses were carried out using the Data Analysis Pak in Excel 5.0 and the nonparametric tests by the primer program of Glantz
• Two-tailed P value of less than 5% was required for statistical significance
• All P values refer to comparisons between groups (not between baseline and end), unless otherwise indicated.

Timing of Measurements

• All patients received instruction in the National Cholesterol Education Program Step 1 diet by the hospital dietitian before beginning the dietary phase.
  • All subjects were urged to maintain a stable lifestyle, including diet, exercise, smoking and alcohol consumption throughout the trial

•  All clinic visits occurred in the morning after a 12 hour fast
• Subjects were instructed to consume no alcohol in the 24 hours before each clinic visit.

Dependent Variables

• Adverse Events
  • Reported spontaneously by the subject or elicited through open (non-leading) questioning.
  • Seriousness
    • Serious
    • Unexpected
    • Both
    • None
  • Severity (according to WHO)
    • Severe
    • Moderate
    • Mild
  • Relation to the trial medication rated by the investigators
    • Probable
    • Possible
    • Unlikely
    • Definitely not
• Lipids
  • Both institutions participated in the Lipid Standardization Program of the Centers for Disease Control and Prevention
    • Each was standardized for measurement of total cholesterol, TG, and HDL cholesterol
    • Both determine LDL concentrations by Lipid Research Clinics methods (beta-quantification)
    • Cholesterol and TG concentrations were measured by enzymatic methods in Kansas City
    • HDL chlesterol was measured by the same enzymatic mathods after precipitation of ApoB-containing lipoproteins with magnesium and dextran sulfate.
    • All samples generated at each center were analyzed at that center.
    • Serum ApoA-1 was measured by immunonephelometry using a Beckman nephelometer in New York and by immunoturbidity using the Cobas Mira in Kansas City.
    • Serum ApoB-100 was not measureable because of the extreme turbidity of many samples.
    • All samples from a given individual were analyzed in the same run
    • The interassay and intra-assay coefficients of variation are < 5% for both assays.
  • ApoE genotyping was performed in New York on samples from all patients, by means of the polymerase chain reaction (PCR) method using the HhaI restriction enzyme.
  • Plasma phopholipid fatty acid composition and concentration for samples from both centers were analyzed in Kansas City
    • The plasma lipids were extracted according to the method of Bligh and Dyer and separated by thin-layer chromatography.
    • Dipheptadecanoyl-phosphotidyl choline was added to the serum sample for an internal standard to allow for calculation of serum concentration of phospholipid-bound fatty acids.

Independent Variables

• Four capsules Omacor per day
• Placebo

Control Variables

Initial N:

• Placebo: N=20
• Omacor: N=22

Subject characteristics at baseline (Week 0,mean±SD)¹

¹ For serum TG, cholesterol and HDL cholesterol, baseline was the mean of values obtained at visits -2, -1 and 0.

² Median vlues were 9.50 and 9.24 mmol/L (841 and 818 mg/dl), respectively.

Attrition (final N): same as above

Age: see above

Ethnicity: not discussed

Other relevant demographics: not discussed

Anthropometrics see above

Location: Conducted simultaneously at two sites: the University of Kansas Medical center and Columbia Presbyterian Medical Center

 Serum Lipids, Lipoproteins and Apoproteins 

• The mean percent change in TG values (baseline to end):
  • Omacor: -45±23%
    • 18/22 subjects responded with a > 35% reduction in TG levels
    • 4/22 subjects had a < 15% reduction
  • Placebo: 16±35%
  • P<0.0001
  • Although the effect was slightly greater at 4 months than 1 month (-45% and -40%), the difference between 4 and 1 month values was not statistically significant.
• VLDL cholesterol
  • Reduction of 32% (P=0.001)
• LDL cholesterol
  • Increase of 32% (P=0014)
  • LDL concentrations were significantly lower at baseline in the Omacor group  because of the chance allocation to this group of 6 subjects with LDL concentrations < 1.30 mmol/L (50 mg/dl) while only 1 subject was included in the placebo group.
  • Omacor group
    • 1 month: 2.64 mmol/L (102 mg/dl)
    • 4 months: 2.69 mmol/L (104 mg/dl)
• HDL cholesterol
  • Omacor group:
    • Increased by 13±19% (P=0.004)
• Ratio of total choleserol to HDL cholesterol
  • Omacor group
    • Decreased by 20% (P=0.0013)
• Serum ApoA-I concentration
  •  No significant differences between the groups.
• ApoE genotypes
  • None of the subjects had type III hyperlipoproteinemia

Effects of Omacor and placebo on selected serum phospholipid fatty acids (percent of total fatty acids) [mean±SD]

*P<0.02 placebo compared with Omacor at 4 months

**P<0.001 placebo compared with Omacor at 1 and 4 months, and baseline compared with 4 months within the Omacor group.

• After both 1 and 4 months of treatment, Omacor increased serum EPA and DHA concentrations 2-3 fold.
• The omega-3 fatty acids appeared to replace the principal omega-6 fatty acids (linoleic and arachidonic), which were significantly decreased,
• When used to assess compliance, the fatty acid results could be expressed either as a percent of total phospholipid fatty acids (in which case EPA concentrations increased from baseline by 193%) or as a concentration (µmol/L) [EPA concentrations increased by 163%].

Side Effects

• 7 subjects reported some form of gastrointestinal problem (not including "burping a fishy taste" during the 4 month trail
  • Placebo=3
  • Omacor=4
• No side effect judged as "probably or possibly reltaed to treatment" was considered to be serious by the investigators
• No subject discontinued treatment because of side effects
• Omacor had no impact on an of the safety panel parameters measured including glucose, hemoglobin A1c, liver enzymes, kidney function and platelet counts.

Other Findings

Compliance and body weight

• Overall compliance average 94% (range 66-100%), with no differences noted b etween groups
• The additional 4 gm oil per day did not significantly alter body weights from baseline within groups (0.4 kg change with placebo; -0.1 kg change with Omacor).

• Treatment of severely hypertriglyceridemic subjects with four capsules of Omacor daily markedly reduced serum triglyceride and cholesterol concentrations and raised HDL cholesterol concentrations.
• No important adverse effects were noted.
• Omacor may be an important addition to the pharmaceutical armamentarium for the treatment of severe increases in TG concentrations.

Study was supported by a grant from Pronova Biocare, Oslo, Norway. The last author is affiliated with Pronova Biocare.

No sample size calculation.

Randomization procedure not described.

How were investigators blinded to treatment group assignment? Were the Omacor capsules and corn oil capsules similar in appearance?

What did dietary assessment consist of? Did the diet change during run in phase and during the study? Did the same RD at each site conduct the assessment? No description of dietary changes, if any, during the study.

How was the Omacor administered? Once daily or multiple times per day? With meals?

Did the vitamin E (18 mg) in the Omacor have any effect on the results?

Short term study (16 weeks)