Perfusion by Arterial Spin Labelling Following Single Dose Tadalafil in Small Vessel Disease (PASTIS) Trial

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

55 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-09-30

Study Completion Date

2018-01-25

Brief Summary

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Could Tadalafil improve blood flow in deep brain tissue and potentially improve cognitive function in patients with cerebral small vessel disease

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Detailed Description

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Cerebral small vessel disease (SVD) is the primary cause of vascular cognitive impairment (VCI), which in its most severe form manifests as vascular dementia (VaD). SVD is a fibrous thickening of small penetrating arteries in deep brain nuclei (basal ganglia, thalami) and subcortical white matter.Clinical studies suggest that pure VCI/VaD contributes approximately 8-15% of dementia in older people Reduced CBF is well established in VCI. Improved blood flow in the vasculature of the deep white and grey matter is therefore an attractive mechanism for slowing the pathology of VCI and is a valuable biomarker for an initial proof of concept study.

To increase the likelihood of success in a full scale clinical trial of tadalafil in VCI, this study will test the effects of single dose tadalafil on cerebral blood flow in subjects with SVD using ASL-MRI. A strict definition of SVD will be used that combines clinical and MRI criteria.

Phosphodiesterase-5 (PDE5) specifically degrades cGMP within cells; limiting activation of protein kinase G. Guanylyl cyclase enzymes generate cGMP, downstream from NOS-nitric oxide signalling.

PDE5 inhibitors in SVD. PDE5 blockade is a plausible strategy to improve local cerebral blood flow (CBF), in the deep brain areas afflicted by SVD. By augmenting the NO-cGMP-PKG pathway, PDE5i drugs are expected to be vaso-relaxant in small artery myocytes.

In patients with pulmonary hypertension sildenafil improved cerebral vascular reactivity in response to hypercapnic challenge, indicative of an improvement in neurovascular coupling. Similar increased reactivity was recorded 60 min after administration of sildenafil in ED patients. By contrast, healthy volunteers showed no change in MCA blood flow following sildenafil, similar to healthy rodents, where vasodilation occurred only at high concentrations of drug. Overall it appears that PDE5i may have little effect on "healthy" cerebral arteries in rodents and humans.

Prior human studies have been single dose studies of PDE5i in healthy humans, have only used sildenafil and have in general estimated CBF from Middle Cerebral Artery (MCA) blood flow using Trans Cranial Doppler (TCD). MCA blood flow may not reflect local blood flow in the microvasculature of the deep white and deep grey matter. One study examined the effect of single dose sildenafil on CBF using SPECT in patients with vascular risk factors with or without a history of stroke. Non-stroke patients exhibited an overall increase in CBF. However, no distinction was made in this study between large vessel and lacunar stroke.

In summary, pre-clinical studies support a CBF-enhancing action of PDE5i in cerebrovascular disease, while human studies to date have been limited to sildenafil and have not specifically addressed effects on CBF in people with SVD.

Tadalafil (Cialis®) is widely-used as an oral agent for sexual dysfunction. As an inhibitor of the enzyme PDE5, tadalafil has a well-established pharmacological profile as a small vessel vasodilator. Side-effect profile and pharmacokinetics are well known and the drug is well-tolerated in the target population, over a range of oral doses and regimens. The choice of tadalafil over other PDE5 inhibitors (such as sildenafil, Viagra®) is based on potency, selectivity for PDE5, plasma half-life and documented brain penetration.

Phosphodiesterase-5 (PDE5) specifically degrades cGMP within cells; limiting activation of protein kinase G. Guanylyl cyclase enzymes generate cGMP, downstream from NOS-nitric oxide signalling. The PDE5 inhibitor sildenafil (Viagra®; discovered at Pfizer, Sandwich UK) raised the profile of PDE5 as a therapeutic target. Tadalafil (Cialis®; licence holder: Eli Lilly) is widely prescribed on an "as required" basis for ED in men. It is also licensed for regular daily use at a dose of 5 mg for benign prostatic hyperplasia and 40 mg for pulmonary hypertension. Tadalafil is well tolerated and its side effect profile is well-established

Conditions

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Dementia, Vascular

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

PREVENTION

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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Active Treatment

Tadalafil 20mg Capsule Stat single dose 2 x MRI scans (pre and post dose) Neuropsychological tests pre and post IMP dose Cognitive functioning prior to 1st MRI scan of that visit

Group Type ACTIVE_COMPARATOR

Tadalafil

Intervention Type DRUG

single dose, 20 mg capsule p.o.

Cognitive functioning tests

Intervention Type BEHAVIORAL

Cognitive function tests will be performed prior to MRI scan 1 performed prior to IMP dosing on 2 occasions as patient will act as their own control

Neuropsychological tests

Intervention Type BEHAVIORAL

Neuropsychological tests will be performed prior to pre IMP dose MRI scan \& then parallel V2 of the tests repeated 3-5 post IMP dose and before 2nd MRI scan.

Participants act as own controls as 1 IMP occasion will be placebo- 2nd IMP occasion will be active. 7-30 days apart

MRI Scan - Arterial Spin Labelling

Intervention Type OTHER

Pre and post IMP dose on 2 occasions to detect difference in blood flow in deep brain 4 MRI scans in total

Control

Matched placebo Capsule Stat single dose 2 x MRI scans (pre and post dose) Neuropsychological tests pre and post IMP dose Cognitive functioning prior to 1st MRI scan of that visit

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

single dose, matching capsule p.o.

Cognitive functioning tests

Intervention Type BEHAVIORAL

Cognitive function tests will be performed prior to MRI scan 1 performed prior to IMP dosing on 2 occasions as patient will act as their own control

Neuropsychological tests

Intervention Type BEHAVIORAL

Neuropsychological tests will be performed prior to pre IMP dose MRI scan \& then parallel V2 of the tests repeated 3-5 post IMP dose and before 2nd MRI scan.

Participants act as own controls as 1 IMP occasion will be placebo- 2nd IMP occasion will be active. 7-30 days apart

MRI Scan - Arterial Spin Labelling

Intervention Type OTHER

Pre and post IMP dose on 2 occasions to detect difference in blood flow in deep brain 4 MRI scans in total

Interventions

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Tadalafil

single dose, 20 mg capsule p.o.

Intervention Type DRUG

Placebo

single dose, matching capsule p.o.

Intervention Type DRUG

Cognitive functioning tests

Cognitive function tests will be performed prior to MRI scan 1 performed prior to IMP dosing on 2 occasions as patient will act as their own control

Intervention Type BEHAVIORAL

Neuropsychological tests

Neuropsychological tests will be performed prior to pre IMP dose MRI scan \& then parallel V2 of the tests repeated 3-5 post IMP dose and before 2nd MRI scan.

Participants act as own controls as 1 IMP occasion will be placebo- 2nd IMP occasion will be active. 7-30 days apart

Intervention Type BEHAVIORAL

MRI Scan - Arterial Spin Labelling

Pre and post IMP dose on 2 occasions to detect difference in blood flow in deep brain 4 MRI scans in total

Intervention Type OTHER

Other Intervention Names

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Cialis TOPF, NIHSS, MoCA, CANTAB, BMIPB, RBANS subtest

Eligibility Criteria

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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:

1. lacunar stroke syndrome with symptoms lasting \>24 hours, occurring at least 6 months previously; OR:
2. 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

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

18\. Known monogenic causes of stroke e.g.. CADASIL

19 Unable to provide informed consent

20\. enrolled in another CTIMP study

Minimum Eligible Age

55 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No