L-Citrulline in Peripheral Artery Disease

NCT02521220 | Completed DMC

• 1 other identifier: CIPER2015UM
• Study Type: interventional
• Target: 49
• Locations: 2 countries
• Sites: 3

Brief Summary

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.

Conditions

Peripheral Arterial Disease

Keywords

L-citrulline; Endothelial dysfunction

Outcome Measures

Primary Outcomes (1)

• Absolute claudication distance

  Measurement of absolute claudication distance using a treadmill exercise test

  30 weeks

Secondary Outcomes (1)

• Endothelial function using endo-PAT (peripheral arterial tone)

  30 weeks

Other Outcomes (2)

• L-citrulline metabolites

  30 weeks

• Walking impairment questionnaire

  30 weeks

Study Arms (2)

L-citrulline

EXPERIMENTAL

Oral food-supplemental amino-acid L-citrulline. 2 times 3g per day.

Dietary Supplement: L-citrulline

Maltodextrin

PLACEBO COMPARATOR

Maltodextrin as placebo. 2 times 3g per day

Dietary Supplement: Placebo

Interventions

L-citrulline DIETARY_SUPPLEMENT

L-citrulline 2 times daily 3 gram (6g/day)

L-citrulline

Placebo DIETARY_SUPPLEMENT

Maltodextrin 2 times daily 3 gram (6g/day)

Maltodextrin

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years or older males and postmenopausal women;
• male participants must agree to using an adequate form of contraception during the study period;
• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Maastricht University: lead
• Clinical Trial Center Maastricht B.V.: collaborator
• Catharina Ziekenhuis Eindhoven: collaborator
• Hannover Medical School: collaborator

Study Sites (3)

Hannover Medical School

Hanover, Germany

Location

Maastricht University

Maastricht, Limburg, 6229, Netherlands

Location

Catharina Ziekenhuis Eindhoven

Eindhoven, Netherlands

Location

MeSH Terms

Conditions

Peripheral Arterial Disease

Interventions

Citrulline

Condition Hierarchy (Ancestors)

Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Peripheral Vascular Diseases

Intervention Hierarchy (Ancestors)

Amino Acids, Diamino; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Harald Schmidt, Prof.

  Maastricht University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: August 10, 2015
• First Posted: August 13, 2015
• Study Start: August 1, 2016
• Primary Completion: February 20, 2019
• Study Completion: August 30, 2019
• Last Updated: September 19, 2019

Record last verified: 2019-09

Locations

DE (1); NL (2)