Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT04088240 |
| Other study ID # |
1907850505 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 4, 2019 |
| Est. completion date |
January 31, 2021 |
Study information
| Verified date |
February 2024 |
| Source |
University of Arizona |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Elevated plasma triglycerides (TG) are due to an excess of TG-rich lipoproteins of several
different types, most commonly of very-low-density lipoproteins (VLDL), but also
intermediate-density lipoproteins (IDL, or VLDL remnants), chylomicrons, and/or chylomicron
remnants. Epidemiologic evidence that a moderate elevation in TG is often associated with
increased atherosclerotic cardiovascular disease (ASCVD) risk, and more recent evidence from
Mendelian randomization studies has shown that elevated TG associated with genetic variants
may be a causal factor for ASCVD and possibly for premature all-cause mortality.[1-6] Fasting
plasma TG concentrations may be categorized as: normal (< 150 mg/dL ), borderline (150-199
mg/dL), high TG (HTG, 200-499 mg/dL), and very high TG (VHTG, ≥ 500 mg/dL).[7, 8] Risk of
acute pancreatitis is increased in VHTG patients, especially those with TG ≥ 1000 mg/dL.[9]
For VHTG, the primary goal of therapy is to reduce TG to < 500 mg/dL,[10] whereas there is no
specific treatment goal for HTG nor prescription indication. However, the omega-3 fatty
acids, EPA and DHA have well-established efficacy in reducing TG in the range of 150-500 when
administered at doses of > or = 3 g/d EPA+DHA (reviewed in Skulas-Ray et al. in press).
Importantly, administration of omega-3 fatty acids to people with TG in this range lead to a
25% reduction in major adverse cardiovascular endpoints in the recently completed "Reduction
of Cardiovascular Events with EPA Intervention Trial" (REDUCE-IT).[11]
The results of REDUCE-IT provide compelling evidence for the use 3 g/d omega-3 fatty acid
supplementation to reduce cardiovascular risk among patients with TG 150-500 mg/dL. The
concentrated EPA supplement used in REDUCE-IT is just one of three long chain n-3 omega-3
fatty acids that influence lipids and lipoproteins and other aspects of cardiovascular risk.
Most research has focused on the evaluation of EPA and DHA, which are the two predominant n-3
FA in fish and in n-3 agents, but docosapentaenoic acid (DPA) is present in fish oil, as
well, and accumulates in the blood at similar concentrations. The carbon length of the n-3 FA
appears important for physiological effects. EPA has a carbon length of 20, DHA has a carbon
length of 22, and DPA, the metabolic intermediate of EPA and DHA, is a 22-carbon n-3 FA. DPA
may have significant potential for treating HTG and VHTG,[12, 13] but research on this fatty
acid remains limited. In a 2-week open-label crossover comparison of 4 g/d of a DPA
concentrate (containing unspecified amounts of free DPA and EPA) vs. 4 g/d EPA concentrate in
people with HTG, plasma TG were reduced 33% by the DPA concentrate, which was significantly
more than the 11% reduction with EPA.[13] Thus, a recent scientific advisory from the
American Heart Association (Skulas-Ray et al, in press) concluded that more research is
needed to elaborate the lipid and lipoprotein effects of DPA.
Additional biomarker research suggests DPA similarly can influence health outcomes that
respond to EPA and DHA. For instance, decreased serum concentrations of DPA and DPA + DHA
have been associated with increased risk of risk of acute coronary events[14] and myocardial
infarction[15], respectively. Plasma DPA was also inversely associated with incident
cardiovascular disease (CVD) in some ethnic groups.[16]
In conclusion evidence supports a potential role of DPA in improving health, but results from
clinical supplementation studies are needed to clarify the effect of DPA supplementation on
lipids and lipoproteins as well as other cardiovascular disease risk factors-relative to
supplementation with EPA and DHA-to ascertain whether enrichment of omega-3 concentrates with
DPA could offer health benefits above and beyond concentrates that only contain EPA and DHA.
Description:
This is a cross-over, double-blind, randomized, placebo-controlled clinical study. Each
treatment phase will span a continuous 6-week period. Prior to the first treatment phase,
participants will be assigned to receive the DPA enriched n-3 supplement, conventional n-3
supplement, and identical placebo in random order. A computer program will be used to
randomly assign participants to a treatment sequence. After each treatment phase,
participants will have a 2-week washout period before beginning the next treatment phase.
Intervention protocol and study treatments:
Study capsules will be provided bi-weekly at the Food, Bioactives, & Health Lab on the
University of Arizona campus or the Collaboratory. Participants may schedule pick-up times
that are most suitable for their schedules. A staff member will be available to meet with
participants at each bi-weekly pick-up.
The treatments are as follows:
- 4 g/d DPA enriched n-3 concentrate (~980 mg DPA, 380 mg EPA, 1720 mg DHA)
- 4 g/d n-3 control (~980 oleic acid, 380 mg EPA, 1720 mg DHA)
- 4 g/d placebo control ("light" olive oil)
For each 6-week treatment phase, participants will consume 4 g/day of the DPA-enriched
concentrate, n-3 matched control, or placebo control. Participants will be required to avoid
consuming any other food or supplements that contain n-3 FA during treatment phases. They
will also be asked to maintain their current dietary intake (with the exception of excluding
additional n-3 containing foods or supplements) and maintain their physical activity level
and body weight over the course of the study.
Each supplementation period will be at least 6 weeks in length. However, treatment periods
can be extended by 2 weeks (up to 8 weeks total) to accommodate scheduling challenges due to
illness, travel, etc. For example, should a participant be unable to come in on two separate
mornings for testing after 6 weeks of supplementation, they may continue the supplement and
schedule testing for the following week.
Screening:
Potential participants will be interviewed by telephone to determine their initial
eligibility. If they remain eligible after the telephone screening, they will be further
screened at the Collaboratory, CATS, or the Food, Bioactives, & Health Lab. This screening
visit will consist of: filling out forms (informed consent, medical history, personal
information); measuring height and weight so body mass index (BMI) can be calculated; and
measuring blood pressure (BP). If it is determined that they are still eligible following
these measurements, a blood sample will be taken and a complete blood cell count, health
panel including liver and kidney function, and a blood fat panel will be performed
(approximately 15 mL of blood or ~1 tablespoon will be taken). If the initial blood draw is
unsuccessful, it may need to be repeated, with permission of the participant. Females of
child-bearing age will be given a urine pregnancy test. Study investigators will review all
of the screening data. Participants meeting eligibility criteria will be scheduled for
baseline data collection and supplementation will begin thereafter.
Baseline and endpoint visits (4 total):
Participants will undergo additional clinical assessments for one day at baseline (screening
values will be used as the second measure) and two days for each of 3 endpoint visits (at the
end of each 6-week treatment phase). The baseline visit will be scheduled within 2 weeks of
the participant's screening visit. Participants will be required to fast overnight (12 hours
with no food or drink except water) and abstain from alcohol for 48 hours prior to each
testing day. To ensure participant eligibility, a brief assessment will be administered (see
ScreeningForm_DPA). If a participant does not meet the requirements, their visit will be
rescheduled. Testing will be conducted at CATS, the Collaboratory, or the Food, Bioactives, &
Health Lab and the procedures are described in more detail below.
• Blood sampling: Prior to having their blood taken, participants will be asked not to
consume any food or drink except water for 12 hours and to avoid alcohol for 48 hours.
Participants also should not engage in vigorous physical activity for 12 hours prior to
having their blood taken. Two blood samples will be taken at baseline and at the end of each
treatment phase (for a total of 8 times after eligibility screening). On two separate days, a
blood sample will be taken from the participant's arm after a 12-hour fast (no food or drink
except water). If the initial blood draw is unsuccessful it may need to be repeated, with the
participant's permission. Approximately 60 mL (4 tablespoons) of blood will be collected at
baseline and at the end of each treatment phase, over two days separated by at least 24
hours. This will be collected as ~52 mL on one day and ~7.5 mL on the other day. Throughout
the entire study, blood will be taken 8 times for a total amount of ~247 mL (~16.5
tablespoons), including the blood taken for screening tests prior to the start of the study
(~15 mL or 1 tablespoon).
- At the end of each testing period, blood will be tested for the following: glucose,
insulin, triglycerides, HDL-C, non-HDL-C, and concentrations of inflammatory markers.
Red blood cell fatty acid concentrations will also be measured to assess compliance.
- On an additional day at the end of each testing period, participants will provide a
blood sample (~7.5 mL) to repeat lipid measurements, which can vary day-to-day.
Blood samples will be stored and analyzed after all participants have completed the study.
Study results will be available after study completion (which may take 2 years or longer).
- Saliva Collection: Saliva samples will be collected using the passive drool technique.
Participants will use the collection aid to pool saliva into a specialized 2 mL
cryovial.
- Urine Pregnancy Testing: Female participants of childbearing age will be asked to
provide a urine sample for pregnancy testing at baseline and at the end of each
treatment phase. If a participant becomes pregnant, she will not be able to continue
participating in the study.
- Pulse Wave Analysis (PWA): On one of the testing days for the baseline visit and at the
end of each supplementation period, participants will undergo testing to measure their
blood pressure and pulse waveforms. This will be assessed using the SphygmoCor System
(AtCor Medical, Sydney, Australia). SphygmoCor testing will be performed prior to the
fasting blood sample and at a consistent time (± 1 hour) for all baseline and endpoint
visits. The PWA measurement is very similar to a routine blood pressure measurement and
will be used to assess central blood pressure and wave reflection characteristics
(augmentation index). These will be derived from brachial pressure waveforms using a
validated generalized transfer function. PWA measurements will be taken following JNC7
blood pressure guidelines in a quiet, temperature-controlled, dimly lit room following a
5-minute seated rest period. Participants will be asked to sit quietly with their feet
flat on the floor for at least 5 minutes. A blood pressure cuff will then be placed on
the upper arm. The cuff will inflate, then deflate for 5 seconds, and then partially
re-inflate. Participants will be asked to remain quiet and still during this
measurement. The procedure will be repeated twice, for a total of 3 measurements, with
approximately 1 minute of rest between each measurement. The last 2 results will be
averaged to increase accuracy.
- Pulse Wave Velocity (PWV): Following the PWA measurement, participants will undergo an
assessment of aortic stiffness, by measuring their carotid-femoral pulse wave velocity
(PWV). For this measurement, participants will be asked to lay flat on a hospital bed
without a pillow. Carotid and femoral arterial pressure waveforms will be measured
simultaneously via an applanation tonometry sensor manually held in place above the
right common carotid artery and a blood pressure cuff placed on the right common femoral
artery. PWV will be calculated by dividing the linear distance between the carotid and
femoral sites by the transit time using SphygmoCor system software. This test will be
performed three times with approximately 1 minute between measurements, and the last 2
results will be averaged to increase accuracy.
- Heart Rate Variability (HVR): Following the PWV measurement, participants will undergo
an assessment of cardiovascular health, by measuring their heart rate variability (HRV).
For this measurement, participants will be asked to lay flat on a hospital bed without a
pillow. Participants will be connected to the SphygmoCor system by 3 ECG leads placed on
the upper torso. HRV information will be collected using SphygmoCor system software.
This test will be performed three times with approximately 1 minute between
measurements, and the last 2 results will be averaged to increase accuracy.
Midpoint Visits:
Supplements will be provided every 3 weeks at a designated study site on the University of
Arizona campus or at the Collaboratory. Participants may schedule pick up times that work
best with their schedule. A study staff member will be available at each pick up visit to
meet with participants to answer questions or discuss side effects.
It will take approximately 22-28 weeks for participants to complete this research study. The
total time for study visits at the Collaboratory, CATS, or the Food, Bioactives, & Health Lab
after initial screening, is approximately 8 hours. Times may vary and pre-menopausal females
will require an additional 5 minutes for a urine pregnancy test at screening, baseline, and
the end of each treatment period. The following is an estimate of the amount of time
participants will spend in study activities:
Screening appointment:
- Forms, blood pressure, and blood draw: 45-60 minutes
- Pregnancy testing (pre-menopausal females only): 5 minutes
Baseline:
- Endpoint testing:
- Blood draw: 15 minutes
- Saliva collection: 5 minutes
- PWA/PWV/HRV testing: 45 minutes
- Pregnancy testing (pre-menopausal females only): 5 minutes
- Second day of testing: (NA; lipid measurements from screening appointment will be used)
End of treatment periods 1, 2, and 3:
- Endpoint testing:
- Blood draw: 15 minutes
- PWA/PWV/HRV testing: 45 minutes
- Pregnancy testing (pre-menopausal females only): 5 minutes
- Second day of testing:
- Blood draw: 15 minutes
- Saliva collection: 5 minutes *Day 1 and 2 measurements may be switched to
accommodate participant schedules
- Visits every 3 weeks to pick up new supplements and return unused capsules: 15
minutes/visit (~90 minutes total)
- Daily consumption logs (completed at home): ~15 minutes total
Total time commitment: ~8-9 hours (8 visits for testing and approximately 6 visits to pick-up
supplements, as well as completing logs at home) over the course of 22-28 weeks.
