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Trial registered on ANZCTR


Registration number
ACTRN12609000882224
Ethics application status
Approved
Date submitted
29/05/2009
Date registered
9/10/2009
Date last updated
9/07/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
Pharmacological effects of oral L-citrulline and tetrahydrobiopterin in patients with peripheral artery disease
Scientific title
Pharmacological effects of oral L-citrulline and tetrahydrobiopterin in patients with peripheral artery disease: effects on walking distance, arterial and endothelial function.
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peripheral artery disease 4880 0
Condition category
Condition code
Cardiovascular 252149 252149 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment regime involves 3 stages with L-citrulline, tetrahydrobiopterin (BH4) and 1 wash out period between Treatments 1 and 2. There is no wash out period between Treatments 2 and 3. Volunteers will participate in all 3 treatment stages.
Treatment 1: either L-citrulline or placebo; 3g powder in sachets taken twice a day for 12 weeks
Wash out period: 4 weeks followed by a cross-over design
Treatment 2: either L-citrulline or placebo; 3g powder in sachets taken twice a day for 12 weeks
Treatment 3: all volunteers receive a combination of L-citrulline (3g powder in sachets taken twice a day) and BH4 (50mg per tablet, 3 tablets taken 3 times a day) for two weeks.
Intervention code [1] 236667 0
Treatment: Drugs
Comparator / control treatment
Maltodextrin (3g powder in sachets taken twice a day) is used for placebo. Placebo will be given during either treatment 1 or 2 for 12 weeks. All volunteers will receive placebo for 12 weeks as this is a cross-over study.
Control group
Placebo

Outcomes
Primary outcome [1] 238047 0
Walking distance will be determined with:
walking impairment questionnaire and treadmill exercise testng using the Skinner-Gardner protocol.
Timepoint [1] 238047 0
At the end of each 12-week treatment with L-citrulline or placebo (cross over design).
At the end of 2-week combined treatment with L-citrulline plus BH4.
Secondary outcome [1] 242225 0
Pulse wave velocity: aorto-femoral pressure waveforms will be recorded using applanation tonometry in order to calculate pulse wave velocity.
Timepoint [1] 242225 0
At the end of each 12-week treatment with L-citrulline or placebo (cross over design).
At the end of 2-week combined treatment with L-citrulline plus BH4.
Secondary outcome [2] 242226 0
Flow-mediated vasodilation: relative diameter change of the brachial artery during reactive hyperaemia will be measured using a high resolution ultrasound unit.
Timepoint [2] 242226 0
At the end of each 12-week treatment with L-citrulline or placebo (cross over design).
At the end of 2-week combined treatment with L-citrulline plus BH4.
Secondary outcome [3] 242227 0
Ankle brachial index: ankle systolic blood pressure will be determined with a continuous Doppler unit, which is then compared with the brachial systolic blood pressure. The ratio of the ankle systolic blood pressure to that in the arm is then calculated.
Timepoint [3] 242227 0
At the end of each 12-week treatment with L-citrulline or placebo (cross over design).
At the end of 2-week combined treatment with L-citrulline plus BH4.
Secondary outcome [4] 242229 0
Inflammatory markers (C-reactive protein(CRP), plasminogen activator inhibitor 1 (PAI1)): these markers will be measured using plasma collected from the whole blood after 12 hours of fasting.
Timepoint [4] 242229 0
At the end of each 12-week treatment with L-citrulline or placebo (cross over design).
At the end of 2-week combined treatment with L-citrulline plus BH4.
Secondary outcome [5] 242230 0
Oxidative stress markers (8-isoprostane) will be measured using plasma collected from the whole blood after 12 hours of fasting.
Timepoint [5] 242230 0
At the end of 12 weeks treatment with L-citrulline or placebo (crossover design).
At the end of 4 weeks combined treatment with L-citrulline plus BH4.
Secondary outcome [6] 242231 0
Endogenous nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA) will be measured using plasma collected from the whole blood after 12 hours of fasting.
Timepoint [6] 242231 0
At the end of 12 weeks treatment with L-citrulline or placebo (crossover design).
At the end of 4 weeks combined treatment with L-citrulline plus BH4.
Secondary outcome [7] 242232 0
Phosphorylation of vasodilator stimulated phosphoprotein (p-VASP), a downstream nitric oxide synthase (NOS) target will be measured using plasma collected from the whole blood after 12 hours of fasting.
Timepoint [7] 242232 0
At the end of 12 weeks treatment with L-citrulline or placebo (crossover design).
At the end of 4 weeks combined treatment with L-citrulline plus BH4.

Eligibility
Key inclusion criteria
Male and postmenopausal women
6 months of stable intermittent claudication
Peripheral artery disease (PAD) secondary to atherosclerosis
Resting ankle brachial index (ABI) <0.9 and at least 25% decrease with exercise
Capacity to walk more than 2 but less than 12 mins on a treadmill
<25% difference in walking distance on treadmill exercise test between 2 baseline studies
No change in medications or physical activity within 3 months of enrollment
Minimum age
40 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Women of child-bearing potential;
Current enrollment in another clinical trial and/or ingestion of another trial agent within 30days of enrollment;
Peripheral artery disease (PAD) of non-atherosclerotic nature;
Fontaine class IV (4);
Leg amputation above ankle;
Peripheral vascular surgery, sympathectomy, angioplasty and/or stent insertion within previous 3 months;
Myocardial infarction, unstable angina, percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery within pervious 3 months;
Uncontrolled hypertension;
Type I diabetes;
Proliferative retinopathy;
History of disease state or surgery affecting gastrointestinal absorption;
Significant renal disease;
Liver disease;
History of treatment for any malignancy within past 5 years or evidence of active malignancy other than squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) of skin;
Serious infection or hypotension associated with sepsis in previous month;
Stroke within past 3 months;
Autoimmune disorder;
Any other acute or chronic medical condition which, in the opinion of the investigator, will increase the liklihood of the subject being unable to complete the study;
Unwillingness to discontinue arginine or citrulline containing products, pentoxifylline, L-carnitine or prostacycline for at least 1 month prior to the study;
Walking distance limited by conditions other than peripheral artery disease (PAD).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation involvine contacting the holder of allocation schedule at central pharmacy
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation by random number generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/07/2009
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 2155 0
3000
Recruitment postcode(s) [2] 2152 0
3150
Recruitment postcode(s) [3] 2154 0
3151
Recruitment postcode(s) [4] 2151 0
3175
Recruitment postcode(s) [5] 2153 0
3805

Funding & Sponsors
Funding source category [1] 5056 0
Government body
Name [1] 5056 0
National Health and Medical Research Council (NHMRC)
Country [1] 5056 0
Australia
Primary sponsor type
Government body
Name
National Health and Medical Research Council (NHMRC)
Address
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country
Australia
Secondary sponsor category [1] 4565 0
Hospital
Name [1] 4565 0
Southern Health
Address [1] 4565 0
Dandenong Hospital
David Street, Dandenong, Victoria 3175
Country [1] 4565 0
Australia
Other collaborator category [1] 693 0
University
Name [1] 693 0
Monash University Centre for Vascular Health
Address [1] 693 0
Wellington Road
Clayton, Victoria, 3168
Country [1] 693 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 239150 0
Southern Health Human Research Ethics Committee
Ethics committee address [1] 239150 0
Southern Health
Clayton Road
Clayton, Victoria, 3168
Ethics committee country [1] 239150 0
Australia
Date submitted for ethics approval [1] 239150 0
01/12/2008
Approval date [1] 239150 0
Ethics approval number [1] 239150 0
08210B

Summary
Brief summary
Aim of Study:
To determine the therapeutic efficacy and effects on arterial function of oral L-citrulline and of the combination of L-citrulline and BH4 in patients with peripheral arterial disease

Background to study:
Loss of the protective actions of L-arginine derived nitric oxide is a cardinal feature of endothelial dysfunction, which contributes to the pathogenesis and progression of cardiovascular disease. Supplementation with L-arginine has been shown to improve vascular function in some but not all clinical studies. Importantly L-arginine bioavailability is low. In contrast L-citrulline, a natural precursor of L-arginine, raises plasma L-arginine levels more effectively. In addition there is a naturally occurring substance called tetrahydrobipterin (BH4) which is a key co-factor in the production of nitric oxide. We believe that there may be additional benefit using the combination (L-citrulline plus BH4). Therefore this study will investigate the clinical effects of oral L-citrulline and combined BH4 supplementation in patients with peripheral arterial disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29667 0
Address 29667 0
Country 29667 0
Phone 29667 0
Fax 29667 0
Email 29667 0
Contact person for public queries
Name 12914 0
Professor Barry McGrath
Address 12914 0
Department of Vascular Sciences
Southern Health
Dandenong Hospital
David Street, Dandenong, Victoria 3175
Country 12914 0
Australia
Phone 12914 0
+61 3 95548025
Fax 12914 0
+61 3 95548027
Email 12914 0
barry.mcgrath@med.monash.edu.au
Contact person for scientific queries
Name 3842 0
Professor Barry McGrath
Address 3842 0
Department of Vascular Sciences
Southern Health
Dandenong Hospital
David Street, Dandenong, Victoria, 3175
Country 3842 0
Australia
Phone 3842 0
+61 3 95548025
Fax 3842 0
+61 3 95548027
Email 3842 0
barry.mcgrath@med.monash.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

Current supporting documents:


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23146Study protocol  hschmidt@ppmlab.net
23147Statistical analysis plan  hschmidt@ppmlab.net
23148Ethical approval  hschmidt@ppmlab.net
23149Analytic code  hschmidt@ppmlab.net

Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbasePharmacology and Clinical Drug Candidates in Redox Medicine.2015https://dx.doi.org/10.1089/ars.2015.6430
Dimensions AIReactive Oxygen-Related Diseases: Therapeutic Targets and Emerging Clinical Indications2015https://doi.org/10.1089/ars.2015.6433
N.B. These documents automatically identified may not have been verified by the study sponsor.