L-Citrulline in Peripheral Artery Disease (CIPER)
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|ClinicalTrials.gov Identifier: NCT02521220|
Recruitment Status : Completed
First Posted : August 13, 2015
Last Update Posted : September 19, 2019
Some studies have reported improved vascular function with the supplementation of L-arginine in participants with cardiovascular disease (CVD). Several clinical studies have also begun the investigation of L-arginine supplementation in participants with peripheral artery disease (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.
The investigators hypothesize that the oral food supplement L-citrulline, unlike L-arginine, reverses endothelial dysfunction. In a multinational, multicenter, double blinded, randomised, placebo-controlled cross-over trial the effects of L-citrulline in peripheral artery disease will be investigated.
|Condition or disease||Intervention/treatment||Phase|
|Peripheral Arterial Disease||Dietary Supplement: L-citrulline Dietary Supplement: Placebo||Not Applicable|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||49 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Beneficial Effects of the Amino-acid Food Supplement L-citrulline in Participants With Peripheral Artery Disease|
|Actual Study Start Date :||August 1, 2016|
|Actual Primary Completion Date :||February 20, 2019|
|Actual Study Completion Date :||August 30, 2019|
Oral food-supplemental amino-acid L-citrulline. 2 times 3g per day.
Dietary Supplement: L-citrulline
L-citrulline 2 times daily 3 gram (6g/day)
Placebo Comparator: Maltodextrin
Maltodextrin as placebo. 2 times 3g per day
Dietary Supplement: Placebo
Maltodextrin 2 times daily 3 gram (6g/day)
- Absolute claudication distance [ Time Frame: 30 weeks ]Measurement of absolute claudication distance using a treadmill exercise test
- Endothelial function using endo-PAT (peripheral arterial tone) [ Time Frame: 30 weeks ]Flow mediated dilation
- L-citrulline metabolites [ Time Frame: 30 weeks ]Blood plasma levels of L-citrulline, L-arginine and asymmetric dimethylarginine (ADMA)
- Walking impairment questionnaire [ Time Frame: 30 weeks ]Assessment of functionality with regard to walking using a questionnaire
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02521220
|Hannover Medical School|
|Maastricht, Limburg, Netherlands, 6229|
|Catharina Ziekenhuis Eindhoven|
|Principal Investigator:||Harald Schmidt, Prof.||Maastricht University|