Clinical trial NCT00931879: 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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypertriglyceridemia
Diabetic Neuropathy
Lead sponsor: Eastern Virginia Medical School
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2009-07-02
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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:

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.

Primary outcomes:
measure: Efficacy Measures Are Nerve Conduction Studies, Specifically Changes in Conduction Amplitude.
timeFrame: One year
measure: Measurements of Indices of Large and Small Fiber Nerve Function Including Heart Rate Variation Measures.
timeFrame: One year
measure: Measurements of Indices of Large and Small Fiber Nerve Function Using Vibration and Thermal Thresholds.
timeFrame: One year
measure: Percent Change in Measurements of Indices of Large and Small Fiber Nerve Function Including Vibration Thresholds
timeFrame: One year
measure: Measurements of Indices of Large and Small Fiber Nerve Function Including Markers of Inflammation and Oxidative Stress.
timeFrame: One year
measure: Efficacy Measures Are Nerve Conduction Studies; Specifically, Increases in Conduction Velocity.
timeFrame: One Year
measure: Efficacy Measures Are Nerve Conduction Studies, Specifically Changes in Latency.
timeFrame: One Year
measure: Efficacy Measures Are Nerve Conduction Studies, Specifically Changes in F-wave Conduction
timeFrame: One Year
measure: Efficacy Measures Examining Increased Vascular Response to Ischemic Block and to Local Warming at the Dorsum of the Foot.
timeFrame: One Year
Secondary outcomes:
Other outcomes:
Locations:
city: Norfolk
country: United States
facility: Strelitz Diabetes Center
state: Virginia
Study officials:
affiliation: Eastern Virginia Medical School
name: Aaron I Vinik, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Eastern Virgina Medical School
name: Henri K Parson, PhD
role: STUDY_DIRECTOR
References: