E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011078 |
E.1.2 | Term | Coronary artery disease |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare vascular function in subjects with coronary artery disease before and after treatment with different doses (400mg or 700mg daily) of 6R-BH4 as assessed by non-invasive MRI. The principal markers of vascular function will be aortic distensibility and pressure pulse wave velocity, carotid artery distensibility and brachial artery flow-mediated dilatation. |
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E.2.2 | Secondary objectives of the trial |
-To assess the effect of 6R-BH4 treatment on the following markers of vascular function in isolated blood vessels: vascular and myocardial superoxide production, nitric oxide-mediated endothelial function by organ bath isometric tension studies. -To assess the effect of 6R-BH4 treatment on biopterin levels in isolated blood vessels. Tertiary Objectives of the trial: -To assess the effect of 6R-BH4 treatment on insulin resistance (fasting glucose & insulin levels) in type II diabetics. -To assess the effect of 6R-BH4 treatment on systemic blood pressure. -To assess the effect of 6R-BH4 treatment on microalbuminuria. -To assess the effect of 6R-BH4 treatment on urinary isoprostane levels. -To assess the effect of 6R-BH4 treatment on: incidence of post-operative AF, length of ITU stay, length of hospital stay, renal function. -To assess the effect of 6R-BH4 treatment on blood markers of oxidative stress and endothelial function. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Male or Female, aged 18 years or above. -Multivessel coronary artery disease scheduled to undergo coronary bypass surgery. -Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study. -Females of childbearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study.
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E.4 | Principal exclusion criteria |
-Pregnant or breastfeeding at screening or planning to become pregnant (subject of partner) at any time during study. -Prior clinical diagnosis of heart failure requiring diuretic treatment with evidence of severe left ventricular dysfunction. -Acute coronary event (unstable angina requiring hospitalisation, myocardial infarction) within the last 4 weeks. -Emergency CABG. -Newly diagnosed diabetes mellitus (<1 month). -Body weight >130 kg. -Impaired renal function (plasma creatinine > 180 µmol/l). -Elevated liver function tests (defined as a serum alanine transaminase (ALT) >50µmol/l (or > 2x normal) and/or AST > 2x normal). -Pacemakers, implantable defibrillators or metal implants that are not compatible with MRI scanning. -Subjects receiving experimental medications or participating in another study using an experimental drug or experimental procedure within 30 days of enrollment into this study. -Subject is terminally ill or is inappropriate for placebo medication. -Any other significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or may influence the result of the study, or the subject’s ability to participate in the study. -Requirements for concomitant treatment with any drug known to inhibit folate metabolism (e.g., methotrexate). -Concomitant treatment with levodopa. -Concomitant treatment with any phosphodiesterase (PDE) 5 inhibitors (e.g., Viagra®, Cialis®, Levitra®, or RevatioTM) or any PDE 3 inhibitor (e.g., cilostazol, milrinone, or vesnarinone) -Subjects previously randomised into this study or any other clinical trial involving 6R-BH4 treatment. -Known allergy or hypersensitivity to any excipient of 6R-BH4.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be the effects of 6R-BH4 (400mg or 700mg daily) compared to placebo on the following MRI parameters of vascular function in subjects with CAD: brachial artery reactivity; aortic distensibility; aortic pressure pulse wave velocity; carotid artery distensibility.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | 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.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial 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
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End of the trial is defined as the six week follow-up telephone contact for the last patient involved in the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 0 |