E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
PARTICIPANTS WITH EVIDENCE OF CEREBRAL SMALL VESSEL DISEASE |
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E.1.1.1 | Medical condition in easily understood language |
Aging and its effects on small arteries in the brain |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
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 Tadalafil increase blood flow in deep brain tissue? |
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E.2.2 | Secondary objectives of the trial |
Does Tadalafil increase blood flow in cerebral cortex grey matter? Does Tadalafil increase cognitive speed and attention? Does plasma tadalafil concentration correlate with changes in brain blood flow? |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria: 1. Radiological evidence of cerebral small vessel disease defined as: MRI evidence of lacunar infarct(s) (≤ 1.5 cm maximum diameter) and/or confluent deep white matter leukoaraiosis (≥ grade 2 on Fazekas scale)
2. Clinical evidence of cerebral small vessel disease can be:
a) lacunar stroke syndrome with symptoms lasting >24 hours, occurring at least 6 months previously; OR:
b) transient ischaemic attack lasting < 24 hours with limb weakness, hemi-sensory loss or dysarthria at least 6 months previously AND with MRI DWI performed acutely showing lacunar infarction, OR if MRI is not performed within 10 days of TIA, a lacunar infarction in an anatomically appropriate position is demonstrated on a subsequent MRI
3. Age ≥ 55 years.
4. Imaging of the carotid arteries with Doppler ultrasound, CT angiography or MR angiography in the previous 12 months, demonstrating < 70% stenosis in both internal carotid arteries |
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E.4 | Principal exclusion criteria |
Exclusion criteria: 1. Known diagnosis of dementia 2. Cortical infarction (>1.5 cm maximum diameter) 3. Systolic BP <90 and/or diastolic BP < 50 4. Creatinine Clearance<50ml/min 5. Severe hepatic impairment 6. History of Lactose intolerance 7. Concomitant use of PDE5 inhibitors e.g. sildenafil, tadalafil, vardenafil. 8. Concomitant use of alpha-blockers e.g. alfuzosin, doxazosin, indoramin, prazosin, tamsulosin, and terazosin can all increase the risk of postural hypotension. 9.Participants receiving nicorandil and nitrates e.g. isosorbide mononitrate, isosorbide dinitrate, glyceryl trinitrate 10. weight > 130kg 11 Uncontrolled cardiac failure 12. Persistent or paroxysmal atrial fibrillation 13. History of gastric ulceration 14. History of ‘sick sinus syndrome’ or other supraventricular cardiac conduction conditions such as sinoatrial or atrioventricular block 15. Uncontrolled COPD 16. Stroke or TIA within the last 6 months 17. MRI not tolerated or contra-indicated : MRI exclusion criteria -Participant has a cardiac pacemaker; recent surgery; vascular clips; metal implants or joint replacements; have had metal fragments in their eyes; has ever worked on a lathe; has shrapnel from a war injury; possibility of pregnancy 18. Known monogenic causes of stroke e.g.. CADASIL 19 Unable to provide informed consent 20. enrolled in another CTIMP study.
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E.5 End points |
E.5.1 | Primary end point(s) |
change in local cerebral blood flow within deep brain nuclei and deep white matter |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Shortly before and 3-5 hours following stat dosing at 2 individual time points (patients are their own controls). |
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E.5.2 | Secondary end point(s) |
Change in regional CBF in cortical grey matter areas. serum [drug concentration] dependence of deep CBF. Changes in neuropsychological parameters including attention and cognitive speed.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Shortly before and 3-5 hours following stat dosing at 2 individual time points (patients are their own controls). |
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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 | No |
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 | No |
E.6.10 | Pharmacogenetic | No |
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 | No |
E.8.1.6 | Cross over | Yes |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | No |
E.8.7 | Trial has a data monitoring committee | No |
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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Tadalafil plasma sample analysis upload into database following last patient, last visit sample |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 31 |