Some studies have reported improved vascular function with the supplementation of L-arginine in participants with CVD. Several clinical studies have also begun the investigation of L-arginine supplementation in participants with PAD. This is…
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Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy parameter is the change in absolute claudication distance
(measured as treadmill-measured maximum walking distance) in the randomized
groups.
Secondary outcome
The secondary efficacy parameters include arterial and endothelial functions
and measurements of the metabolites of L-citrulline metabolism.
Background summary
Peripheral artery disease (PAD) is a common manifestation of atherosclerosis,
narrowing of a blood vessel due to plaque formation. People with PAD have a
higher risk of cardiovascular disease (CVD). Nitric oxide (NO), a chemical
released by endothelial cells (lining cells of the blood vessels), has been
shown to play an important role in PAD and CVD. This is because NO dilates
blood vessels, regulates blood flow and blood pressure and maintains the
integrity of the blood vessel by preventing platelets sticking to the vessel
wall. NO production is regulated by a class of enzymes known as the NO
synthases. These enzymes synthesize NO from its amino acid substrate,
L-arginine in the presence of co-factors.
Loss of the protective actions of NO, a cardinal feature of endothelial
dysfunction, contributes to the development of CVD. Decreased NO production has
been observed under conditions of oxidative stress, a process during which
damaging free radical production is increased. This reduced NO production
through oxidative stress may be harmful as most CVD and related risk factors
coincide with oxidative stress. Finding ways to increase or maintain NO
production is hence important.
Study objective
Some studies have reported improved vascular function with the supplementation
of L-arginine in participants with CVD. Several clinical studies have also
begun the investigation of L-arginine supplementation in participants with PAD.
This is particularly important as currently there are limited options available
to medically manage intermittent leg pain resulted from PAD. Although some of
these short-term clinical trials suggested that oral L-arginine improved
walking distance or improved walking speed in participants with PAD, these
results were not consistent. Further, only 1% of the oral supplemented
L-arginine is available for the NO production as the rest is metabolised by the
body. A better way to provide the body with substrate to produce NO is
therefore needed. The natural amino acid and food component, L-citrulline has
been suggested to be a good candidate for this purpose.
L-citrulline, named after watermelon citrullus vulgaris from which it was first
isolated, is a natural precursor of L-arginine. Studies have shown that
L-citrulline is metabolised by the body to a lesser degree compared to
L-arginine and hence is an effective precursor of arginine in peripheral
tissues, including endothelial cells. Oral L-citrulline supplementation also
eliminates some of the unwanted effects associated with oral arginine
supplementation and it is well tolerated without known side effects. In
addition, L-citrulline is a supplement that is available over-the-counter.
Thus, oral supplementation of L-citrulline may be a new intervention strategy
in participants with PAD.
We hypothesize that the oral food supplement L-citrulline, unlike L-arginine,
reverses endothelial dysfunction.
Study design
The primary aim of this trial is to examine whether the oral food supplement
L-citrulline has any effect on clinical status, walking distance, arterial and
endothelial function in participants with PAD.
We will use a double-blinded crossover design in which patients serve as their
own controls. Patients who are enrolled will have two 'treatment' periods of
twelve weeks with a wash-out period of 4 weeks in between. Patients will be
randomly assigned to get L-citrulline in the first and placebo in the second
period and vice versa.
Intervention
After a screening phase of 3 weeks, there will be a 'zero-point' measurement en
then the first 'treatment' period of 12 weeks starts (placebo or
food-supplement). Then there is a wash-out phase of 4 weeks after which the
second 'treatment' period starts (food-supplement or placebo) In both periods,
after 2 weeks and at the end of the period, a measurement of primary and
secondary outcomes will be done: a questionnaire has to be filled out,
treadmill test and flow-mediated dilation or endo-PAT(for vessel function). The
follow-up will take another 4 weeks and will end with a phone call to check for
the condition of the patient and possible side effects.
Since every patient gets both placebo and the food-supplement, every patient is
his/her own control.
For the patients in the Catharina Hospital in Eindhoven, the treadmill tests
will be performed by the patients treating physiotherapist (part of the
Claudicationet).
Study burden and risks
During the study, patients will take L-citrulline and placebo during 12 weeks.
No side effects or negative effects are expected from taking these substances.
Patients will have to do a few extra visits to the hospital that do not belong
to the standard visits. During the visits, blood will be drawn and the vascular
function will be measured in the fore-arm by using a blood pressure cuff, which
can give an unpleasant feeling.
Treadmill tests will also be performed which can cause the pain/complaints that
the patients also experiences as part of his condition.
Universiteitssingel 50
Maastricht 6229 ER
NL
Universiteitssingel 50
Maastricht 6229 ER
NL
Listed location countries
Age
Inclusion criteria
* 40 years or older males and postmenopausal women;
* male participants must agree to using an adequate form of contraception during the study period;
* 6-month history of stable intermittent claudication (IC) due to PAD;
* PAD secondary to atherosclerosis with significant claudication (Fontaine class II defined as IC, or Fontaine class III defined as pain at rest);
* IC characterised by pain, ache, cramp, numbness or severe fatigue involving muscles of one or both lower extremities, reproducibly provoked by walking and relieved by rest;
* ankle-brachial index (ABI) at rest of <0.9 and at least 25% decrease in ABI within 1 min during exercise recovery;
* capacity to walk more than 2 min/15 meters but no more than 12 min on a treadmill using the Skinner-Gardner protocol;
* walking limited by claudication, not coexisting conditions; and
* difference between two consecutive baseline exercise treadmill tests of <25% during the 3-weeks run-in period; and
* no change in medications or physical activity within 3 months prior to enrolment.
Exclusion criteria
* Women of child-bearing potential;
* Current enrolment in another clinical trial and/or ingestion of another investigational product within the past 30 days before enrolment;
* PAD of non-atherosclerotic nature;
* Fontaine class IV i.e. ulcer or gangrene;
* leg amputation above the ankle;
* peripheral vascular surgery, sympathectomy, peripheral angioplasty or stent insertion within the previous 3 months;
* myocardial infarction, unstable angina, percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery within the previous 3 months;
* uncontrolled hypertension (resting SBP >190 or DBP >115 mmHg);
* hypotension (SBP <90mmHg);
* type I diabetes, proliferative retinopathy;
* history of disease state or surgery that affects gastrointestinal absorption;
* significant renal disease (serum creatinine >3.0 mg/dl);
* liver disease (transaminase > 3x upper limit of normal, bilirubin >1.5 times upper limits of normal);
* history of treatment for any malignancy within the past 5 years, or evidence of active malignancy other than squamous cells or basal cell carcinoma of the skin;
* serious infection or hypotension associated with sepsis in the last month;
* cerebrovascular infarct in the last 3 months;
* autoimmune disorders (e.g. systemic lupus erythematosis, ulcerative colitis);
* any other acute or chronic medical condition that in the opinion of the investigators increases the likelihood that the participant would be unable to complete the study;
* unwillingness to discontinue arginine- or L-citrulline-containing products, pentoxifylline, L-carnitine, or prostacyclin for at least 1 month prior to and during the study; and
* conditions other than PAD that limit walking distance.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT02521220 |
| CCMO | NL54573.100.15 |