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    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2006-001125-26
    Sponsor's Protocol Code Number:ORG322
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-07-23
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2006-001125-26
    A.3Full title of the trial
    A randomised controlled trial of oral l-arginine supplementation on platelet and endothelial function and walking distance in patients with peripheral arterial disease
    A.3.2Name or abbreviated title of the trial where available
    L-ARGININE IN PAD
    A.4.1Sponsor's protocol code numberORG322
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Aberdeen
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namearginine silicate inositol
    D.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typedietary supplement
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboPowder for oral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Peripheral arterial disease
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary aims of proposed study: In patients with peripheral arterial disease, to assess the effects of L-arginine on
    1) platelet activation and
    2 ) endothelial activation as assessed by plasma markers vWF, sE-selectin and VCAM-1, and pulse wave velocity

    E.2.2Secondary objectives of the trial
    Secondary aims: to assess the effect of L-arginine supplementation on treadmill maximal walking distance
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    All patients must be able to give informed consent, have an ABPI<0.8 and be on a statin and aspirin. If patients are not on these medications they will be commenced and enrolled 6 weeks later. We wish to determine the adjuvant effects of L-arginine in patients with PAD on what is considered to be routine medical therapy. All patients in this study will attend our nurse led claudication clinic and strict attention will be paid to secondary risk factor prevention as per our local guidelines.
    E.4Principal exclusion criteria
    Patients with rest pain or ulceration, liver impairment or abnormal platelet count or diabetes and those on clopidogrel, warfarin or non-steroidal anti-inflammatory drugs other than aspirin.
    E.5 End points
    E.5.1Primary end point(s)
    The primary end-points are platelet and endothelial activity. The method of assessment of these end-points is outlined below:


    Blood sampling/Assays: 20 mls blood will be taken through a 21 gauge needle from the ante-cubital vein of rested subjects without the use of tourniquet in order to minimise trauma. The first 5ml of blood will be discarded. The following assays and recordings will be performed at baseline, 3 and 6 weeks..
    Platelets: Flow cytometry and Ultegra platelet tests will be performed immediately.
    • Whole blood flow cytometry: Coulter EPICS Flow Cytometer
    The presence of platelet-monocyte aggregates, expression of P-selectin and fibrinogen binding on platelets will be measured in diluted whole blood samples with and without ex vivo stimulation with ADP, as previously described by our laboratory7.
    • Rapid platelet function assay: [Ultegra] Platelet aggregation in citrated whole blood samples will be analysed using the ASA and TRAP cartridges12,13.

    Markers of endothelial activity: The plasma markers of endothelial activity namely vWF, sE-and P-selectin and VCAM-1 have been shown to be elevated in patients with PAD 5,13,15. A reduction in bioavailabilty of nitric oxide may play a role in the increased levels of these markers. In experimental models, nitric oxide has been shown to inhibit secretion of the endothelial Weibel-Palade bodies which store vWF and P-selectin and down regulate VCAM expression of endothelial cells16,17. These adhesive glycoproteins are esssential for platelet adhesion and aggregation and leucocyte rolling16. Inhibition of nitric oxide release in humans has been shown to result in increased levels of vWF18. Shedding of soluble P-selectin by platelets is also inhibited by nitric oxide19. E-selectin is only expressed on activated endothelium and the soluble form which secreted is thus specific for endothelial function. E-selectin expression in vitro is inhibited by nitric oxide20.
    For the following assays plasma will be stored at -800C until assayed.
    • vWF will be measured by an in-house ELISA using polyclonal rabbit antihuman vWF antibody and horse radish peroxidase-conjugated antibody from Dako Cytomation, Denmark.
    • Soluble P-selectin, E-selectin and VCAM-1 will be measured by ELISA (R & D Systems, Inc, Minneapolis, USA). Previous studies in our laboratory have shown the inter-assay variation to be less than 10%.
    • Blood pressure: measured by the Datascope accutor plus (Datascope Medical company).Three supine blood pressure measurements will be taken 1 minute apart after a 10 minute rest, and the average of these readings will be used in the analysis. This will be recorded just prior to measuring the pulse wave velocity
    • Pulse wave velocity & stiffness index: this will be measured by the fully automated micromedical pulse trace PWV (PT 4000, Rochester, Kent). Pulse wave velocity is measured from the onset of the flow pulse as detected by a 4mHz CW directional doppler at the carotid and femoral pulses. The stiffness index is measured via the use of photoplethysmography.

    L-arginine levels and asymmetrical dimethylarginine: will be determined by high-performance liquid chromatography-mass spectrometry6

    Measurement of maximal walking distance: Gardner variable-grade, constant speed treadmill protocol. For inclusion in the study, patients will be required to walk on a treadmill for at least 1 minute and the variability between 2 consecutive tests at baseline will be required to be less than 25%.

    Quality of life: Generic SF36 and disease specific Charing Cross Questionnaire

    Data analysis: Data will be analysed on an intention to treat basis with subgroup analysis and study findings will be reported in line with CONSORT. The known variations that exist in the population with regard to percentage platelet P-selectin expression and fibrinogen binding will be addressed by examining changes from baseline for each patient. Multiple variable linear regression analysis will be used to compare the primary outcome in the two groups adjusting for confounding factors. The relationship between pulse wave velocity, platelet activation and vWF will also be assessed using multiple linear regression analysis. Statistical expertise will be provided by Gordon Prescott, Senior Lecturer in Medical Statistics, Public Health, University of Aberdeen who also performed the above power calculation.

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial is the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months12
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state56
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 56
    F.4.2.2In the whole clinical trial 56
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    normal treatment of the condition
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2006-08-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-04-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-05-25
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