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Lovaza® and Microvascular Function in Type 2 Diabetes

Primary Purpose

Hypertriglyceridemia, Diabetic Neuropathy

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

omega-3-ethyl esters

Placebo

About this trial

This is an interventional treatment trial for Hypertriglyceridemia

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

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).
Presence of diabetic retinopathy that is more severe than "background" level.
Presence of diabetic nephropathy, defined by urine dipstick results greater than 300 mg/100 mL for protein (proteinuria).
Presence of clinically significant neuropathy that is clearly of non-diabetic origin, e.g. alcoholic or autoimmune.
Bilateral amputation of lower extremities or foot ulcers involving the great toes. Presence of neuroarthropathy (Charcot deformity) is allowable.
History of major macrovascular events such as myocardial infarction or stroke.
Participation in another clinical trial concurrently or within 30 days prior to entry into this study.
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.
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.
Presence of pedal edema.
Presence or history of heart failure New York Heart Association Class II or greater.
Other serious medical conditions that in the opinion of the investigator, would compromise the subject's participation in the study.
Concomitant use of medications known to exacerbate triglyceride levels, such as estrogens.

Sites / Locations

Strelitz Diabetes Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo

omega-3-ethyl esters 4g

Arm Description

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.

Outcomes

Primary Outcome Measures

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

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).

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.

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.

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.

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

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

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

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

Secondary Outcome Measures

Full Information

NCT ID

NCT00931879

First Posted

June 17, 2009

Last Updated

March 28, 2017

Sponsor

Eastern Virginia Medical School

Collaborators

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT00931879

Brief Title

Lovaza® and Microvascular Function in Type 2 Diabetes

Official Title

The Role of Lovaza® on Microvascular Function and Lipoprotein Profile in Type 2 Diabetes

Study Type

Interventional

2. Study Status

Record Verification Date

March 2017

Overall Recruitment Status

Completed

Study Start Date

October 2009 (undefined)

Primary Completion Date

July 2012 (Actual)

Study Completion Date

July 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Eastern Virginia Medical School

Collaborators

GlaxoSmithKline

4. Oversight

Data Monitoring Committee

5. Study Description

Brief 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypertriglyceridemia, Diabetic Neuropathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

44 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Arm Title

omega-3-ethyl esters 4g

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

omega-3-ethyl esters

Other Intervention Name(s)

Lovaza

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Primary Outcome Measure Information:

Title

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

Description

Time Frame

One year

Title

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

Description

Time Frame

One year

Title

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

Description

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

Title

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

Description

Time Frame

One year

Title

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

Description

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

Time Frame

One year

Title

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

Time Frame

One Year

Title

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

Time Frame

One Year

Title

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

Time Frame

One Year

Title

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

Time Frame

One Year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subjects may be males or non-pregnant, non-lactating females age 18-80 years. Subjects must have been diagnosed with type 2 diabetes mellitus according to the current ADA criteria. Triglyceride levels above 149 mg/dL Minimum of 2 years after diagnosis of type 2 diabetes Prior to participation in this study, each subject must sign an informed consent document. Exclusion Criteria: 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). Presence of diabetic retinopathy that is more severe than "background" level. Presence of diabetic nephropathy, defined by urine dipstick results greater than 300 mg/100 mL for protein (proteinuria). Presence of clinically significant neuropathy that is clearly of non-diabetic origin, e.g. alcoholic or autoimmune. Bilateral amputation of lower extremities or foot ulcers involving the great toes. Presence of neuroarthropathy (Charcot deformity) is allowable. History of major macrovascular events such as myocardial infarction or stroke. Participation in another clinical trial concurrently or within 30 days prior to entry into this study. 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. 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. Presence of pedal edema. Presence or history of heart failure New York Heart Association Class II or greater. Other serious medical conditions that in the opinion of the investigator, would compromise the subject's participation in the study. Concomitant use of medications known to exacerbate triglyceride levels, such as estrogens.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Aaron I Vinik, MD, PhD

Organizational Affiliation

Eastern Virginia Medical School

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Henri K Parson, PhD

Organizational Affiliation

Eastern Virgina Medical School

Official's Role

Study Director

Facility Information:

Facility Name

Strelitz Diabetes Center

City

Norfolk

State/Province

Virginia

ZIP/Postal Code

23510

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Lovaza® and Microvascular Function in Type 2 Diabetes

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