Omega 7 + 3 Combination and Systemic Inflammation
Condition: Inflammation
MeSH terms: Inflammation
Study type: Interventional

Summary: 
      The purpose of this study is to determine if supplementation with a mixture of omega 7 and 3
      fats has a favorable influence on blood inflammation and lipoprotein biomarkers in women with
      systemic inflammation compared to omega 3 and placebo.
    

Detailed description: 
      Background Information and Scientific Rationale

      Consumption of long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs), including
      eicosapentaenoic acid (EPA; 20:5n-3), docosapentaenoic acid (DPA; 22:5n-3), and
      docosahexaenoic acid (DHA; 22:6n-3) from fish and fish-oil supplements reduces disease risk
      factors, counters components of the metabolic syndrome including inflammation and high
      triglycerides, stabilizes heart cells, prevents blood clots from forming, and decreases
      all-cause mortality, cardiac and sudden death, and possibly stroke (Circulation
      2006;114:82-96).

      The health benefits of n3-PUFAs have prompted the U.S. Food and Drug Administration (FDA) to
      support a qualified health claim status for EPA and DHA. Estimates are that the ratio of
      omega-6 (n-6) linoleic acid (LA) to omega-3 (n-3) α-linolenic acid (ALA; 18:3n-3), ALA
      increased from 6.4 to 10.0 during the 20th century, resulting in decreased tissue
      concentrations of EPA and DHA (Am J Clin Nutr 2011;93:950-962). Recommendations for EPA and
      DHA intake vary, but in general, most organizations recommend a range of 300 to 1,000 mg/day
      from fatty fish and supplements (Circulation 2006;114:82-96). The FDA recommends that
      consumers not exceed 3,000 mg/day of EPA and DHA, with no more than 2,000 mg/day from a
      dietary supplement.

      The persistent increase in inflammation biomarkers is defined as chronic or systemic
      inflammation, and is linked with multiple disorders and diseases including atherosclerosis
      and cardiovascular disease (CVD), the metabolic syndrome (MetS), and diabetes mellitus
      (Circulation 2003;107:499-511). C-reactive protein (CRP) is the most frequently measured
      inflammatory biomarker, and individuals with CRP values in the upper tertile of the adult
      population (>3.0 mg/L) have a 2-fold increase in CVD risk compared to those with a CRP
      concentration below 1.0 mg/L (Curr Atheroscler Rep 2010;12:110-8). An elevated fasting IL-6
      concentration is a significant component of the chronic low-grade inflammation (Metabolism
      2007;56:332-8). Epidemiological studies suggest an inverse relationship between CRP and a
      diet rich in marine products (Am J Clin Nutr 2006;84:223-9). At sufficiently high intakes,
      n-3 PUFAs may decrease the production of inflammatory eicosanoids and cytokines (Mol Nutr
      Food Res 2008;52:885-97). The majority of intervention studies in adults with features of
      MetS report a benefit for some inflammatory measures, but other studies using high n-3 fatty
      acid doses and long supplementation periods have reported no effect (for review, see Lipids
      2013;48:319-32). A pre-existing inflammatory state or a poor n-3 PUFA status may be required
      to see a benefit of n-3 PUFAs on systemic inflammation.

      Palmitoleic acid (C16:1 n-7) is an omega-7 monounsaturated fatty acid that is found in
      macadamia nuts and the seeds of a variety of plants including cat's claw, sea buckthorn, and
      milk weed (Prog Lipid Res 2012;51:340-9). Macadamia nuts are the only practical source for
      palmitoleic acid (30%). The nutritional and biological functions of palmitoleic acid are
      complex and scientific understanding of the biological significance on human health is
      limited (J Lipid Res 2011;52:808-12; Curr Opin Clin Nutr Metab Care. 2013;16:225-31).
      Palmitoleate may increase cell membrane fluidity, attenuate insulin resistance, and reduce
      inflammation associated with diabetes and heart disease (for review, see Prog Lipid Res
      2012;51:340-9). Several human studies indicate that supplementation and/or inclusion of
      macadamia nuts in a cholesterol-lowering diet significantly reduces LDL-C concentrations
      (4.0-10.7%) and triglyceride concentrations (9.0-20.9%) (see J Nutr 2008;138:761-7; Arch
      Intern Med 2000;160:1154-8). One human study with 17 male hypercholesterolemia subjects
      showed that supplementation with macadamia nuts for a period of 4 weeks reduced plasma
      biomarkers for inflammation and oxidative stress (Lipids 2007;42:583-7).

      Study Product (A) Placebo Placebo (EEs)- MCT (medium chain triglyceride) and manufactured by
      Natural Factors. All subjects will receive one softgel orally twice daily with food.

      Study Product (B): Omega-3 fatty acid ethyl esters, 2 soft gels of total 1000mg (660mg EPA
      +340mg DHA)/day EPA/DHA product manufactured by Natural Factors. Each softgel of Omega-3
      contains 500 mg of a natural marine lipid concentrate (330 mg eicosapentaenoic acid [EPA],
      170 mg docosahexaenoic acid [DHA]). All subjects will receive one softgel orally twice daily
      with food.

      Study Product (C): Omega-3 fatty acid + Omega-7 fatty acid Cis-Palmitoleic acid, ethyl
      esters, 2 soft gels of total 1000mg (660mg EPA +340mg DHA) of Omega-3 + 210mg of Omega-7
      fatty acid /day

      All subjects will receive one soft gel orally twice daily with food.

      Potential Risks and Benefits

      Potential Risks of the products All of these fatty acids are found naturally in whole foods
      such as macadamia nuts, fish, or meat. The omega 3 supplements in this study do not exceed
      the upper levels recommended by the FDA (3,000 mg/day of EPA and DHA, with no more than 2,000
      mg/day from a dietary supplement). For comparison, one 3-oz serving of wild Atlantic salmon
      provides about 1,500 mg of EPA and DHA, and a 3-oz serving of canned white tuna provides 700
      mg. Fish oil supplementation has an established history of safe use as a nutritional
      supplement and as a medical food.

      Palmitoleic acid is a monounsaturated fat that is in macadamia nuts. The purified omega 7 fat
      to be used in this study is derived from Peruvian anchovies, and concentrated through a
      seven-step purification process to 50% palmitoleic acid. In an unpublished randomized, double
      blinded, placebo controlled study, the omega 7 + 3 combination exerted anti-inflammatory and
      lipid modulating effects, and was well tolerated among participants with no adverse effects
      (Dr. Andrew Swick, Metagenics, private communication, February 13, 2014).

      Potential Benefits Potential health benefits include improvements in plasma lipoproteins and
      reductions in systemic inflammation with omega 7 + 3 combination and omega 3 fats.

      Study Objectives/Endpoints This is a single center, placebo controlled, double blinded, 8
      week, 3-arm randomized controlled trial conducted at the Appalachian State University Human
      Performance Laboratory at the North Carolina Research Campus in Kannapolis, NC. All patients
      will undergo informed consent process before enrollment.

      This is an exploratory study with generally healthy female subjects to obtain information
      pertaining to efficacy of omega 7 + 3 combination in improving systemic inflammation and
      plasma lipoproteins compared to omega 3 fats alone and placebo.

      The primary Study Objectives/Endpoints are:

      To explore the effects of 8-weeks supplementation with omegas 7 and 3 fats combination versus
      omega-3 fats and placebo on systemic inflammation (CRP and cytokine panel).

      Secondary Study Objectives/Endpoints are:

      To explore the effects of 8-weeks supplementation with omegas 7 and 3 fats combination versus
      omega-3 fats and placebo on plasma lipoproteins.

      Study Design Screening/Orientation: This is a double-blinded, placebo-controlled randomized
      clinical study to assess the effects of placebo (A) and Omega-3 (B) and Omega-7 and Omega-3
      combination (C) in the subjects. Approximately 68 female subjects between the ages of 18 and
      70 years and with a BMI of 25 and higher who meet study entrance criteria will be entered
      into the study and randomized to one of three groups (A,B, or C). The goal is for 60 women to
      finish all phases of the study. The purpose of the screening/orientation visit is to
      determine volunteer eligibility for study participation. Screening will include review and
      signing of the consent form; measurement of height, weight, and body composition; completion
      of the medical history questionnaire and review of medical history and current medications;
      completion of the symptom log; and collection of 8 hour fasting blood samples for testing of
      CRP. Based on previous experience, approximately 100 women will have to be screened to
      identify 60-68 subjects with a CRP of 2 mg/L and higher. Women with a CRP below 2 mg/L will
      receive an email message indicating that they do not meet study criteria, but will receive
      results from the CRP test.

      Clinical Visits:

      Total length of participation in the study, including screening, will be approximately 10
      weeks. Subjects will meet with the study manager at all lab visits. During the lab visits,
      the study manager will review questionnaires for signs and symptoms of adverse events, review
      compliance to the study product and lifestyle, and answer any questions from the subject.
      Blood samples will be collected, and body weight and composition measured at all visits. Body
      composition will be assessed through leg-to-leg bioelectrical impedance using a Tanita scale.

      Supplement schedule: All subjects will ingest 1 soft gel (either A, B, or C) twice daily with
      morning and evening meals for 8 weeks. If a subject fails to ingest supplements at a given
      meal or day, they will be asked to double up intake to get back on schedule. Subjects failing
      to take supplements for three days in a row or longer will be asked to contact the research
      manager to review whether or not they should continue in the study. Subjects will maintain
      their current lifestyles - including diet, and exercise without change during trial
      participation. Subjects will be instructed not to make changes to their use of prescribed
      medications. Acetaminophen may be used as rescue for headaches and associated symptoms during
      study participation. The research manager will make sure the subjects are maintaining use of
      group A, B, or C study soft gel supplements by email between the visits. Subjects must agree
      to maintain normal dietary and physical activity patterns during the study, make no formal
      attempts to lose body weight, limit fish and seafood to no more than one serving per week,
      and limit intake of omega-6 fatty acids by lowering use of corn, soybean, safflower,
      sunflower, and similar oils, and substituting moderate amounts of olive and canola oil.

      Visit 1 (Day 0) is defined as the day of enrollment and administration of the first study
      product. Subjects meeting all criteria including CRP levels of 2 mg/L and higher will return
      to the ASU-NCRC Human Performance Laboratory and receive a 28-day supply of capsules (A,B, or
      C). The consent form and medical questionnaire will be reviewed. A 28-day retrospective
      symptom log will be filled in. Weight and body composition will be assessed on the Tanita BIA
      scale. A blood sample will be collected, with serum sent to the Carolina Medical Center for
      CRP and lipid panel analysis. Plasma aliquots (EDTA tubes) will be prepared and frozen at
      -80°C for post-study NMR lipoprotein analysis at LipoScience (Raleigh, NC), cytokine analysis
      (7-plex MSD panel) at the North Carolina Research Campus, and fatty acid analysis at the
      Lipid Labs LLC (Austin, Minnesota).

      Visit 2 (Week 4) and Visit 3 (Week 8):

      Study procedures from Visit 1 will be repeated. Compliance will be assessed through the
      return of unused capsules.
    

Intervention name(s): Omega 7 + 3; Omega 3; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): Ingestion of omega 7 + 3 daily for 8 weeks.; Omega 3 daily for 8 weeks.; Medium chain triglycerides
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: inflammation; lipoproteins; omega 3; omega 7