Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00284076 |
| Other study ID # |
357 |
| Secondary ID |
T32HL007708P50HL |
| Status |
Completed |
| Phase |
N/A
|
| First received |
January 27, 2006 |
| Last updated |
March 4, 2014 |
| Start date |
February 2000 |
| Est. completion date |
July 2006 |
Study information
| Verified date |
March 2014 |
| Source |
Stanford University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Federal Government |
| Study type |
Interventional
|
Clinical Trial Summary
To assess the effects of L-arginine upon functional status (treadmill exercise testing;
quality of life) and limb blood (by mercury strain gauge plethysmography) in peripheral
arterial disease.
Description:
BACKGROUND:
Peripheral arterial disease is a common disorder effecting up to 15% of men over age 55 and
women over age 65. Patients with peripheral arterial disease are at increased risk for
stroke, myocardial infarction or other adverse vascular outcomes. Therapy for this disorder
is currently limited with only 2 FDA approved drugs (Pentoxifylline, cilostazol). These
agents improve walking distance by 10 to 40 percent. Other agents such as verapamil and
prostacyclin analogs have significant side effects. Although therapy with angiogenesis
inducers, including injections of plasmid constructs for vascular endothelial growth factor
(VEGF) or VEGF protein, is beneficial, the widespread applicability of this therapy is
questionable. The study used an alternative approach, which may be safer and more effective.
The basis for this approach is the ability of L-arginine to enhance endogenous vascular
nitric oxide production, improving blood flow acutely. Furthermore, since several angiogenic
growth factors may act at least partially through the production of nitric oxide, this
therapy could produce a sustained benefit by the induction of an increase in skeletal muscle
capillary density.
DESIGN NARRATIVE:
A randomized placebo-controlled trial to assess the effects of L-arginine on functional
status was performed in patients with peripheral arterial disease. Blood flow was assessed
by Doppler and plethysmography and measures of nitric oxide synthesis (plasma and urinary
nitrogen oxides) were performed. The effect of L-arginine on treadmill walking distance was
determined. The potential for L-arginine induced angiogenesis was assessed using magnetic
resonance angiography.
There were two separate studies of oral L-arginine. The first was a dose ranging study
involving 80 patients receiving four different doses of L-arginine (9 grams, 6 grams, 3
grams, or 0 grams). The dosing of L-arginine was performed in a randomized
placebo-controlled fashion. Patients receive six weeks of therapy. Patients with diabetic
retinopathy, active malignancy or previous malignancy in a state of remission, or autoimmune
disorders were excluded. Ophthalmological exams were performed to screen for pathological
angiogenesis in the retina. After the completion of the dose response study, the
investigators studied the safety and efficacy of prolonged (12 months) L-arginine therapy.
The primary end point was absolute claudication distance (ACD) and a statistical analysis
was performed of the logarithm ACDT / ACDB. A treadmill was performed at one month after
cessation of therapy to determine if there was a structural alteration of the indices of
limb hemodynamics including the ankle brachial index (ABI) and plethysmography was performed
at 6 and 12 months of therapy and at 1 month after sensation of therapy. The study
correlated measures of limb blood flow with evidence of increased nitric oxide synthesis by
measuring urinary nitrogen oxide. Flow mediated vasodilation (FMVD) of the brachial artery
was measured. The choice of monitoring flow mediated vasodilation of the brachial artery,
while appropriate for showing a systemic enhancement of nitric oxide synthesis, would not
directly support an improvement of endothelial function in the vascular bed of interest.
Asymmetric dimethylarginine (ADMA) was measured with the prediction that patients with
elevated ADMA levels, depressed urinary nitrogen oxides and reduced FMVD might be more
responsive to L-arginine therapy. A second aim of the protocol was to determine if the
chronic enhancement of nitric oxide synthesis by L-arginine supplementation had an enduring
effect on conduit vessel structure. The ankle brachial index, plethysmography, and MR
perfusion imaging were performed at 0, 6 and 12 months on therapy, and at 1 month after
cessation of therapy.
