E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
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 |
Does the angiotensin II receptor antagonist, Irbesartan, reduce the rate of aortic dilatation in patients with Marfan Syndrome compared to placebo? |
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E.2.2 | Secondary objectives of the trial |
• Change in z score per year, where the z score is calculated on aortic root and body surface area (BSA). • Clinical events and requirement for surgery including aortic dissection confirmed on TOE, MRI or CT, aortic dissection requiring emergency surgery, aortic dissection requiring elective surgery, aortic dilatation requiring elective or emergency surgery, death (all cause and classified by suspected cause), cerebrovascular accident, cardiovascular death, aortic regurgitation requiring surgery, death during surgery for any of the above. • Left ventricular function determined by volumes and ejection fraction. • Left ventricular mass measurements. • Assessment of valvular function. • Cardiac rhythm and voltage • Height, weight, arm span and lower segment measurements. • Fibrillin-1 mutation analysis will be performed in those patients whose mutation status is unknown. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1.Genetics sub study (1) Fibrillin 1 mutation analysis. If patients consent separately, the mutation will be analysed to investigate the correlation between mutation and drug response. (2) Pharmacogenetics analysis- A case control association sub study where selected variants in key candidate genes are genotyped and their relationship with Irbesartan efficacy established. 3. TGF-b sub study - To assess the mechanism by which AT1 blockade antagonizes TGF-b signalling. |
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E.3 | Principal inclusion criteria |
1. Clinically confirmed MFS using the Ghent diagnostic criteria 2. 2. Aorta dilated above the 95% normal confidence limits (using accepted methods) 3. Provision of informed consent 4. From 6 ≥ to ≤ 40 years of age inclusive
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E.4 | Principal exclusion criteria |
1. Previous cardiac or aortic surgery 2. Planned cardiac or aortic surgery at the time of randomisation 3. Aortic diameter >=4.5cm 4. Haemodynamically significant, severe valvular disease (at the judgement of the treating clinician) 5. Heart failure, defined as left ventricular ejection fraction < 40% 6. Therapeutic use of ACE inhibitors/angiotensin-II receptor antagonist 7. Previous recorded adverse reaction to the trial medication (Irbesartan) or any ACE inhibitor/angiotensin-II receptor antagonist 8. Female patients who are pregnant, planning pregnancy or not using reliable contraception 9. Impaired renal function defined as estimated creatinine clearance <60ml/minute, or serum creatinine >150micromol/litre |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure will be the absolute change in aortic root diameter per year measured by echocardiography. Echo measurements will be taken by transthoracic echocardiograms performed at baseline and annually thereafter in order to assess the annual change of aortic dilatation. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Information not present in EudraCT |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Information not present in EudraCT |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 21 |
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 | Yes |
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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The end of trial is considered to be the last patient last visit (LPLV) whereby the final echocardiogram will be undertaken for the primary outcome analysis |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |