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CompletedNCT00931879Updated May 9, 2017Results posted

Lovaza® and Microvascular Function in Type 2 Diabetes

A Phase 4 interventional study of omega-3-ethyl esters and Placebo in Hypertriglyceridemia and Diabetic Neuropathy, sponsored by Eastern Virginia Medical School. Completed at 1 site in United States. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2017-05-09.

Sponsored by Eastern Virginia Medical School · Phase 4, Interventional, and Treatment

Phase
Phase 4
Study type
Interventional
Enrollment
44
Allocation
Randomized
Ages
18 Years to 80 Years
Sex
All
01

Study summary

The objective of this study is to determine the efficacy of 6 months of 4 g/day oral Lovaza® on endothelial-dependent and heat-induced vasodilation in type 2 diabetics with neuropathy and elevated triglyceride levels. Omega-3 fatty acids appear to exert beneficial effects on vascular function that are independent of the changes in serum triglycerides. The efficacy will be compared with a placebo given at the same duration. Efficacy of the drug will be evaluated after 3 and 6 months of treatment. This timeline should be adequate for evaluation of the primary neurophysiological endpoints. Previously, the investigators have demonstrated that it is feasible to pharmacologically alter nerve fiber density in as little as 18 weeks and that this correlates with subjective and objective measures of neurovascular function. The investigators are predicting an enhancement of post-ischemic hyperemia of the foot dorsum, where the dilative mechanism is primarily endothelium-dependent and a similar improvement in heat-induced hyperemia.

Read the detailed description

This pilot study is a within-subject repeated measures design. This study will compare the neurophysiological and vascular responses to placebo and treatment with Lovaza® (omega-3-acid ethyl esters, Reliant Pharmaceuticals, Inc.) in subjects with type 2 diabetes, neuropathy, and dyslipidemia.

Lovaza's potential mechanism of action is the inhibition of acyl Coenzyme A:1, 2-diacylglycerol acyltransferase and increased peroxisomal β-oxidation in the liver.

Subjects will be recruited and a baseline of physiological, neurological and hematological profile established for each patient. Forty-four subjects (20 in the active arm, 20 in the placebo arm, and 2 replacements for each arm) will receive 4 g/day Lovaza® tablets or placebo for a period of 6 months. All subjects will receive a physical and neurological exam as well as neurovascular function testing. This includes nerve conduction studies, quantitative sensory testing, quantitative autonomic testing, and skin blood flow testing, which includes, ischemia reperfusion. Lab tests include an insulin resistance profile, hepatic and renal function profiles, lipid profile, C-reactive protein, thyroid stimulating hormone, and fatty acids. Other tests include inflammatory markers such as adiponectin and tumor necrosis factor-α. The study is powered to detect differences in microvascular function after 6 months of Lovaza® and differences in ethnic responses.

02

Conditions studied

  • Hypertriglyceridemia
  • Diabetic Neuropathy
03

In context

Diabetic Neuropathies

617 studies on the registry are indexed under Diabetic Neuropathies; 91 are open to participants now.

This study's enrollment of 44 is below the median of 73 across 510 interventional studies indexed under Diabetic Neuropathies.

Browse Diabetic Neuropathies studies →

Lead sponsor

Eastern Virginia Medical School is the lead sponsor of 56 studies on the registry; 8 are open to participants now.

Of its 9 completed or terminated interventional studies of FDA-regulated products, 1 (11%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 80 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Subjects may be males or non-pregnant, non-lactating females age 18-80 years.
  2. Subjects must have been diagnosed with type 2 diabetes mellitus according to the current ADA criteria.
  3. Triglyceride levels above 149 mg/dL
  4. Minimum of 2 years after diagnosis of type 2 diabetes
  5. Prior to participation in this study, each subject must sign an informed consent document.

Exclusion criteria

Exclusion Criteria:

  1. Presence of type 1 diabetes mellitus (defined as C-peptide \< 1 ng/ml or diabetes onset at \< 35 years of age in a non-obese patient).
  2. Presence of diabetic retinopathy that is more severe than "background" level.
  3. Presence of diabetic nephropathy, defined by urine dipstick results greater than 300 mg/100 mL for protein (proteinuria).
  4. Presence of clinically significant neuropathy that is clearly of non-diabetic origin, e.g. alcoholic or autoimmune.
  5. Bilateral amputation of lower extremities or foot ulcers involving the great toes. Presence of neuroarthropathy (Charcot deformity) is allowable.
  6. History of major macrovascular events such as myocardial infarction or stroke.
  7. Participation in another clinical trial concurrently or within 30 days prior to entry into this study.
  8. The use of ACE-inhibiting agents or angiotensin receptor blockade therapy (ARB) is allowed but must have been stable for at least 30 days prior to study entry and may not change during the course of the study. This is prudent due to their potential effects on blood flow.
  9. Patients with moderate or severe hepatic insufficiency or abnormalities of liver function defined as any liver enzymes (aspartate aminotransferase,alanine transaminase, alkaline phosphatase) greater than 3 times the upper limit of normal.
  10. Presence of pedal edema.
  11. Presence or history of heart failure New York Heart Association Class II or greater.
  12. Other serious medical conditions that in the opinion of the investigator, would compromise the subject's participation in the study.
  13. Concomitant use of medications known to exacerbate triglyceride levels, such as estrogens.
05

Study design

Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Care provider, Investigator)
Enrollment
44 participants (actual)

Study arms

  • Placebo comparator
    Placebo

    Subjects are males or non-pregnant, non-lactating females age 18-80 years. All subjects must have been diagnosed with type 2 diabetes mellitus a minimum of two years according to the current ADA criteria and triglyceride levels above 149 mg/dL. Subjects in this arm will be taking placebo for 6 months.

    Drug: Placebo

  • Active comparator
    omega-3-ethyl esters 4g

    Subjects are males or non-pregnant, non-lactating females age 18-80 years. All subjects must have been diagnosed with type 2 diabetes mellitus a minimum of two years according to the current ADA criteria and triglyceride levels above 149 mg/dL. Subjects in this arm will be taking 4 g of Lovaza per day for 6 months.

    Drug: omega-3-ethyl esters

Interventions

  • Drugomega-3-ethyl esters

    Lovaza (TM) (omega-3-ethyl esters) 1 gram Capsules are indicated as an adjunct to diet to reduce very high (\>500 mg/dL) triglyceride (TG) levels in adult patients.

    Also known as: Lovaza

  • DrugPlacebo

    Subjects are males or non-pregnant, non-lactating females age 18-80 years. All subjects must have been diagnosed with type 2 diabetes mellitus a minimum of two years according to the current ADA criteria and triglyceride levels above 149 mg/dL. Subjects in this arm will be taking placebo for 6 months.

06

What researchers measure

Primary outcomes

  1. Efficacy Measures Are Nerve Conduction Studies, Specifically Changes in Conduction Amplitude.

    19 participants in each arm( placebo or omega-3-ethyl esters 4g) were analyzed . Conduction velocities and amplitude of the following nerves were compared between each arm: Tibial Nerve Ankle Amplitude, Tibial Nerve Popliteal Amplitude, Median Nerve Wrist Amplitude, Median Nerve Elbow Amplitude, Peroneal Motor Nerve Ankle Amplitude, Peroneal Motor Nerve Below Fibular Amplitude, Peroneal Motor Nerve Above Fibular Amplitude, Sensory Median Nerve Wrist Amplitude, Sensory Ulnar, Sensory Sural Ankle Ampltiude Wrist Ampltiude

    Time frame: One year

  2. Measurements of Indices of Large and Small Fiber Nerve Function Including Heart Rate Variation Measures.

    Quantitative Autonomic Function Tests (QAFTs) were performed. Primarily, power spectral analysis of heart rate variability (HRV) and time- and frequency-domain analyses, including measures of the sympathetic and parasympathetic control of the heart beat (R-R interval), were recorded with deep breathing, Valsalva, and standing from the sitting position maneuvers. Additionally, the sample difference of the beat to beat (NN) intervals and the TSP was calculated as well as the standard deviation of all normal R-R intervals (sdNN).

    Time frame: One year

  3. Measurements of Indices of Large and Small Fiber Nerve Function Using Vibration and Thermal Thresholds.

    Quantitative Sensory Tests (QSTs), including, cold sensation threshold, cold pain threshold and vibration detection threshold, were used to evaluate peripheral sensory perception.

    Time frame: One year

  4. Percent Change in Measurements of Indices of Large and Small Fiber Nerve Function Including Vibration Thresholds

    Quantitative Sensory Tests (QSTs), including vibration detection threshold, were used to evaluate peripheral sensory perception. Mean represents percent change of total group. Measurements taken at baseline and at one year.

    Time frame: One year

  5. Measurements of Indices of Large and Small Fiber Nerve Function Including Markers of Inflammation and Oxidative Stress.

    Oxidative stress/inflammatory markers (IL1β, IKKβ, TLR4, TNF-α, JNK1, toll-like receptor 2) were assessed through a meal challenge.

    Time frame: One year

  6. Efficacy Measures Are Nerve Conduction Studies; Specifically, Increases in Conduction Velocity.

    Time frame: One Year

  7. Efficacy Measures Are Nerve Conduction Studies, Specifically Changes in Latency.

    Time frame: One Year

  8. Efficacy Measures Are Nerve Conduction Studies, Specifically Changes in F-wave Conduction

    Time frame: One Year

  9. Efficacy Measures Examining Increased Vascular Response to Ischemic Block and to Local Warming at the Dorsum of the Foot.

    Time frame: One Year

07

Results

Posted May 9, 2017

Participant flow

Participant flow — Overall Study
MilestonePlaceboLovaza
Started2222
Completed1919
Not completed33

Outcome measures

PrimaryEfficacy Measures Are Nerve Conduction Studies, Specifically Changes in Conduction Amplitude.

19 participants in each arm( placebo or omega-3-ethyl esters 4g) were analyzed . Conduction velocities and amplitude of the following nerves were compared between each arm: Tibial Nerve Ankle Amplitude, Tibial Nerve Popliteal Amplitude, Median Nerve Wrist Amplitude, Median Nerve Elbow Amplitude, Peroneal Motor Nerve Ankle Amplitude, Peroneal Motor Nerve Below Fibular Amplitude, Peroneal Motor Nerve Above Fibular Amplitude, Sensory Median Nerve Wrist Amplitude, Sensory Ulnar, Sensory Sural Ankle Ampltiude Wrist Ampltiude

Time frame:
One year
Reported as:
Mean · uV
Efficacy Measures Are Nerve Conduction Studies, Specifically Changes in Conduction Amplitude.
uVPlaceboOmega-3-ethyl Esters 4g
Tibial Nerve Ankle Amplitude7.28 ± 0.947.14 ± 1.13
Tibial Nerve Popliteal Amplitude4.08 ± 0.583.80 ± 0.73
Median Nerve Wrist Amplitude6.89 ± 0.607.24 ± 0.55
Median Nerve Elbow Amplitude5.21 ± 0.566.06 ± 0.58
Peroneal Motor Nerve Ankle Amplitude2.97 ± 0.472.55 ± 0.36
Peroneal Motor Nerve Below Fibular Amplitude2.70 ± 0.462.17 ± 0.32
Peroneal Motor Nerve Above Fibular Amplitude2.79 ± 0.462.11 ± 0.31
Sensory Median Nerve Wrist Amplitude22.96 ± 3.0426.56 ± 5.09
Sensory Ulnar Wrist Ampltiude26.93 ± 3.3921.65 ± 5.13
Sensory Sural Ankle Ampltiude8.01 ± 1.558.33 ± 1.83
PrimaryMeasurements of Indices of Large and Small Fiber Nerve Function Including Heart Rate Variation Measures.

Quantitative Autonomic Function Tests (QAFTs) were performed. Primarily, power spectral analysis of heart rate variability (HRV) and time- and frequency-domain analyses, including measures of the sympathetic and parasympathetic control of the heart beat (R-R interval), were recorded with deep breathing, Valsalva, and standing from the sitting position maneuvers. Additionally, the sample difference of the beat to beat (NN) intervals and the TSP was calculated as well as the standard deviation of all normal R-R intervals (sdNN).

Time frame:
One year
Reported as:
Mean · ms
Measurements of Indices of Large and Small Fiber Nerve Function Including Heart Rate Variation Measures.
msPlaceboLovaza
Resting sdNN (ms)31.924 ± 15.50940.748 ± 16.050
Resting rmsSD (ms)28.838 ± 15.59272.075 ± 30.165
Deep Breathing sdNN (ms)3.840 ± 10.70311.637 ± 11.426
Deep Breathing rmsSD (ms)20.823 ± 2.46238.136 ± 10.539
Valsalva sdNN (ms)0.136 ± 0.0776.333 ± 13.516
Valsalva rmsSD (ms)12.752 ± 15.51126.668 ± 20.514
Standing sdNN (ms)5.3786 ± 10.3618.622 ± 12.080
Standing rmsSD (ms)23.725 ± 20.55138.243 ± 21.850
PrimaryMeasurements of Indices of Large and Small Fiber Nerve Function Using Vibration and Thermal Thresholds.

Quantitative Sensory Tests (QSTs), including, cold sensation threshold, cold pain threshold and vibration detection threshold, were used to evaluate peripheral sensory perception.

Time frame:
One year
Reported as:
Mean · °C
Measurements of Indices of Large and Small Fiber Nerve Function Using Vibration and Thermal Thresholds.
°CPlaceboOmega-3-ethyl Esters 4g
Cold Sensation Threshold-Finger (°C)0.311 ± 0.4690.221 ± 0.749
Cold Pain Threshold-Finger (°C)-1.167 ± 1.525-1.789 ± 1.882
Cold Sesnation Threshold-Toe (°C)-1.169 ± 1.183-3.763 ± 1.647
Cold Pain Threshold-Toe (°C)5.658 ± 1.906-1.405 ± 2.158
Cold Sensation Threshold-Dorsum (°C)-2.062 ± 1.484-3.768 ± 1.709
Cold Pain Threshold-Dorsum (°C)0.937 ± 2.215-1.739 ± 2.339
PrimaryPercent Change in Measurements of Indices of Large and Small Fiber Nerve Function Including Vibration Thresholds

Quantitative Sensory Tests (QSTs), including vibration detection threshold, were used to evaluate peripheral sensory perception. Mean represents percent change of total group. Measurements taken at baseline and at one year.

Time frame:
One year
Reported as:
Mean · % Change
Percent Change in Measurements of Indices of Large and Small Fiber Nerve Function Including Vibration Thresholds
% ChangePlaceboOmega-3-ethyl Esters 4g
Vibration Detection Threshold-Finger (% Change)-0.375 ± 0.241-1.102 ± 0.309
Vibration Detection Threshold-Toe (% Change)-3.750 ± 5.321-8.169 ± 3.263
PrimaryMeasurements of Indices of Large and Small Fiber Nerve Function Including Markers of Inflammation and Oxidative Stress.

Oxidative stress/inflammatory markers (IL1β, IKKβ, TLR4, TNF-α, JNK1, toll-like receptor 2) were assessed through a meal challenge.

Time frame:
One year
Reported as:
Mean · pg/ml
Measurements of Indices of Large and Small Fiber Nerve Function Including Markers of Inflammation and Oxidative Stress.
pg/mlPlaceboOmega-3-ethyl Esters 4g
IL1β (pg/ml)1.13 ± 0.211.14 ± 0.31
IKKβ (pg/ml)0.98 ± 0.160.96 ± 0.17
TLR4 (pg/ml)1.11 ± 0.181.17 ± 0.29
TNFα (pg/ml)1.18 ± 0.190.76 ± 0.11
JNK1 (pg/ml)0.94 ± 0.150.75 ± 0.21
toll-like receptor 2 (pg/ml)0.90 ± 0.120.87 ± 0.16
PrimaryEfficacy Measures Are Nerve Conduction Studies; Specifically, Increases in Conduction Velocity.
Time frame:
One Year
Reported as:
Mean · m/s
Efficacy Measures Are Nerve Conduction Studies; Specifically, Increases in Conduction Velocity.
m/sPlaceboOmega-3-ethyl Esters 4g
Tibial Nerve Popliteal Conduction Velocity41.08 ± 6.5837.53 ± 1.51
Median Nerve Elbow Conduction Velocity45.89 ± 1.7646.74 ± 1.23
Peroneal Motor Nerve Bel. Fib. Conduction Velocity40.36 ± 1.3539.96 ± 1.31
Peroneal Motor Nerve Abo. Fib. Conduction Velocity44.44 ± 3.6545.00 ± 2.89
Sensory Median Nerve Wrist Conduction Velocity43.76 ± 3.0846.59 ± 1.87
Sensory Ulnar Wrist Conduction Velocity46.94 ± 1.7345.22 ± 1.75
Sensory Sural Ankle Conduction Velocity39.03 ± 1.6138.60 ± 1.57
PrimaryEfficacy Measures Are Nerve Conduction Studies, Specifically Changes in Latency.
Time frame:
One Year
Reported as:
Mean · ms
Efficacy Measures Are Nerve Conduction Studies, Specifically Changes in Latency.
msPlaceboOmega-3-ethyl Esters 4g
Tibial Nerve Ankle Latency5.08 ± 0.285.29 ± 0.31
Tibial Nerve Popliteal Latency14.65 ± 0.5116.41 ± 0.66
Median Nerve Wrist Latency4.81 ± 1.154.56 ± 0.19
Median Nerve Elbow Latency9.16 ± 0.438.79 ± 0.35
Peroneal Motor Nerve Ankle Latency5.77 ± 0.495.24 ± 0.21
Peroneal Motor Nerve Below Fibular Latency13.58 ± 0.7713.20 ± 0.40
Peroneal Motor Nerve Above Fibular Latency15.37 ± 0.9514.92 ± 0.45
Sensory Median Nerve Wrist Latency3.48 ± 0.333.01 ± 0.16
Sensory Ulnar Wrist Latency2.51 ± 0.132.62 ± 0.11
Sensory Sural Ankle Latency3.68 ± 0.153.70 ± 0.14
PrimaryEfficacy Measures Are Nerve Conduction Studies, Specifically Changes in F-wave Conduction
Time frame:
One Year
Reported as:
Mean · m/s
Efficacy Measures Are Nerve Conduction Studies, Specifically Changes in F-wave Conduction
m/sPlaceboOmega-3-ethyl Esters 4g
Tibial Nerve F-Wave Conduction51.14 ± 3.0255.89 ± 2.45
Median Nerve F-Wave Conduction29.46 ± 1.0929.44 ± 0.90
Peroneal Motor Nerve F-Wave Conduction41.96 ± 3.0947.47 ± 2.49
PrimaryEfficacy Measures Examining Increased Vascular Response to Ischemic Block and to Local Warming at the Dorsum of the Foot.
Time frame:
One Year

No measurements were reported for this outcome.

Adverse events

Collected over All adverse event data was collected per individual from time of consent to 6 months after consent.. Non-serious events are listed at a 3% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo—4/19 (21.1%)7/19 (36.8%)
Lovaza—2/19 (10.5%)8/19 (42.1%)
Most frequent serious events
Most frequent serious events
EventPlaceboLovaza
Atypical Chest PainRespiratory, thoracic and mediastinal disorders0/191/19
Head trauma due to accidental fallInjury, poisoning and procedural complications1/190/19
Hospitilization due to low blood pressure and faintingCardiac disorders1/190/19
Overnight stay in ER for observation after experiencing chest painCardiac disorders1/190/19
Planned surgery to treat Achalasia/Esophageal motility disorderSurgical and medical procedures1/190/19
Emergency Surgery to relieve bile duct obstructionSurgical and medical procedures0/191/19
Most frequent other events
Showing 10 of 18
Most frequent other events
EventPlaceboLovaza
Upper Respiratory InfectionRespiratory, thoracic and mediastinal disorders0/191/19
Severe-Moderate DiarrheaGastrointestinal disorders0/191/19
Dehyrdation/Severe Vomiting/DiarrheaGastrointestinal disorders0/191/19
Personal InjuryInjury, poisoning and procedural complications0/191/19
Dizziness/FaintingNervous system disorders0/191/19
Fainting/DizzinessNervous system disorders0/191/19
Eye DischargeEye disorders0/191/19
Cranial/Facial LesionsSkin and subcutaneous tissue disorders0/191/19
Abdominal PainGastrointestinal disorders1/190/19
Bacterial InfectionInfections and infestations1/190/19

Baseline characteristics

The study was powered at 0.80 for a two-tail analysis with a sensitivity of a 30% delta in blood flow in 40 subjects. The standard deviation of the measurements was calculated at 45% of the treatment group mean. This assessment of variance could accommodate for 9% attrition or data loss in the study. 44 patients will be recruited in total.

Age, Continuous
Age, Continuous(years)PlaceboLovazaTotal
Mean60.58 ± 2.0658.21 ± 1.7059.39 ± 1.33
Sex: Female, Male
Sex: Female, Male(Participants)PlaceboLovazaTotal
Female111223
Male8715
Race (NIH/OMB)
Race (NIH/OMB)(Participants)PlaceboLovazaTotal
American Indian or Alaska Native000
Asian000
Native Hawaiian or Other Pacific Islander000
Black or African American123
White171734
More than one race000
Unknown or Not Reported101
Weight (lbs)
Weight (lbs)(lbs)PlaceboLovazaTotal
Mean217.03 ± 9.62215.16 ± 10.38215.71 ± 7.25
BMI kg/m^2
BMI kg/m^2(kg/m^2)PlaceboLovazaTotal
Mean34.04 ± 1.1734.37 ± 1.8334.10 ± 1.11
Qualifying triglyceride level (mg/dL)
Qualifying triglyceride level (mg/dL)(mg/dL)PlaceboLovazaTotal
Mean215.05 ± 12.51261.17 ± 50.73237.48 ± 24.42
Total cholesterol (mg/dL)
Total cholesterol (mg/dL)((mg/dL))PlaceboLovazaTotal
Mean152.26 ± 6.56189.42 ± 9.63170.84 ± 6.51
HDL cholesterol (mg/dL)
HDL cholesterol (mg/dL)((mg/dL))PlaceboLovazaTotal
Mean39.84 ± 2.2743.32 ± 2.8141.58 ± 1.80

8 further baseline measures are reported on the registry.

08

Study locations

1 site
  • Strelitz Diabetes Center
    Norfolk, Virginia 23510, United States
09

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on May 9, 2017, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT00931879
Lead sponsor
Eastern Virginia Medical School
Collaborators
GlaxoSmithKline
Responsible party
Aaron I. Vinik, MD, PhD (Principal Investigator, Eastern Virginia Medical School) — Principal investigator
First posted
Jul 2, 2009
Start date
Oct 2009
Primary completion
Jul 2012
Completion
Jul 2012
Results posted
May 9, 2017
Last update
May 9, 2017

Study contacts

Aaron I Vinik, MD, PhD
principal investigator · Eastern Virginia Medical School
Henri K Parson, PhD
study director · Eastern Virgina Medical School

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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