L-Citrulline in Peripheral Artery Disease

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.

The investigators 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.

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 (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.

The study was completed with 24 patients in Hannover, Germany, and 25 in Melbourne, Australia.

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 systolic blood pressure (SBP) >190 or diastolic blood pressure (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.