Peripheral Arterial DiseaseCIPERNCT02521220
L-Citrulline in Peripheral Artery Disease
A study testing L-citrulline in people with Peripheral Arterial Disease, run by Maastricht University at 3 sites in 2 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- Peripheral Arterial Disease
- What is being tested?
- L-citrulline
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 49 participants
- Where
- 3 sitesin 2 countries
- Study dates
- 1 Aug 2016to 30 Aug 2019
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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;
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- 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.
Who cannot join
- 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;
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- 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.
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
Netherlands2 sites
Catharina Ziekenhuis Eindhoven
Eindhoven
Maastricht University
Maastricht, Limburg, 6229
About this study
Official title: Beneficial Effects of the Amino-acid Food Supplement L-citrulline in Participants With Peripheral Artery Disease
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.
Read the detailed description
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.
- Conditions
- Peripheral Arterial Disease
- Being tested
- L-citrulline, Placebo
- Keywords
- L-citrulline, Endothelial dysfunction
- Medical subject headings
- Peripheral Arterial Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-citrullineDietary supplement
L-citrulline 2 times daily 3 gram (6g/day)
PlaceboDietary supplement
Maltodextrin 2 times daily 3 gram (6g/day)
| Study group | Role | What they receive |
|---|---|---|
| L-citrulline | Experimental | Oral food-supplemental amino-acid L-citrulline. 2 times 3g per day. Receives: Dietary Supplement: L-citrulline |
| Maltodextrin | Placebo comparator | Maltodextrin as placebo. 2 times 3g per day Receives: Dietary Supplement: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Absolute claudication distance
Measurement of absolute claudication distance using a treadmill exercise test
Measured: 30 weeks
Secondary outcomes (1)
Endothelial function using endo-PAT (peripheral arterial tone)
Flow mediated dilation
Measured: 30 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Aug 2015 (estimated)
- Study start1 Aug 2016
- Primary completion20 Feb 2019
- Study completion30 Aug 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Peripheral Arterial DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 49 participants (actual)
Sponsor and investigators
- Lead sponsor
- Maastricht University
- Sponsor type
- University, hospital or other
- Collaborators
- Clinical Trial Center Maastricht B.V., Catharina Ziekenhuis Eindhoven, Hannover Medical School
- Responsible party
- Principal investigator, H. Schmidt, Maastricht University
- Investigators
- Harald Schmidt, Prof., Principal investigator, Maastricht University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02521220
- Sponsor's protocol ID
- CIPER2015UM
- Acronym
- CIPER
- Status last verified
- Sep 2019
- First submitted
- 10 Aug 2015
- Last updated
- 19 Sep 2019
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Beneficial Effects of the Amino-acid Food Supplement L-citrulline in Participants With Peripheral Artery Disease
- ClinicalTrials.gov ID
- NCT02521220
- Acronym / sponsor ID
- CIPER / CIPER2015UM
- Conditions
- Peripheral Arterial Disease
- Keywords
- L-citrulline, Endothelial dysfunction
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 49 participants (actual)
- Lead sponsor
- Maastricht UniversityUniversity, hospital or other
- Collaborators
- Clinical Trial Center Maastricht B.V., Catharina Ziekenhuis Eindhoven, Hannover Medical School
- Study start
- 1 Aug 2016 (actual)
- Primary completion
- 20 Feb 2019 (actual)
- Study completion
- 30 Aug 2019 (actual)
- First posted
- 13 Aug 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| L-citrulline | Experimental | Dietary Supplement: L-citrullineOral food-supplemental amino-acid L-citrulline. 2 times 3g per day. |
| Maltodextrin | Placebo comparator | Dietary Supplement: PlaceboMaltodextrin as placebo. 2 times 3g per day |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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;
Key exclusion criteria (20 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-citrullineL-citrulline 2 times daily 3 gram (6g/day) | Dietary supplement | L-citrulline |
| PlaceboMaltodextrin 2 times daily 3 gram (6g/day) | Dietary supplement | Maltodextrin |
Primary outcome
Absolute claudication distance
Time frame: 30 weeks
Measurement of absolute claudication distance using a treadmill exercise test
1 secondary outcome
Endothelial function using endo-PAT (peripheral arterial tone)
Time frame: 30 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2019.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Harald Schmidt, Prof. principal investigator
Maastricht University
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing L-citrulline in people with Peripheral Arterial Disease, run by Maastricht University at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Netherlands, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Absolute claudication distance (time frame: 30 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2019.