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

S

St George's, University of London

Status and phase

Completed
Phase 2

Conditions

Dementia, Vascular

Treatments

Other: MRI Scan - Arterial Spin Labelling
Drug: Tadalafil
Behavioral: Cognitive functioning tests
Behavioral: Neuropsychological tests
Drug: Placebo

Study type

Interventional

Funder types

Other

Identifiers

NCT02450253
2015-001235-20 (EudraCT Number)
15/LO/0714 (Other Identifier)
14.0189
20140901

Details and patient eligibility

About

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

Full description

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

Enrollment

55 patients

Sex

All

Ages

55+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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:

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

  4. 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

    1. Age ≥ 55 years.

    2. 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

    1. Persistent or paroxysmal atrial fibrillation

    2. History of gastric ulceration

    3. History of 'sick sinus syndrome' or other supraventricular cardiac conduction conditions such as sinoatrial or atrioventricular block

    4. Uncontrolled COPD

    5. Stroke or TIA within the last 6 months

    6. 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

    7. Known monogenic causes of stroke e.g.. CADASIL

    19 Unable to provide informed consent

    1. enrolled in another CTIMP study

Trial design

Primary purpose

Prevention

Allocation

Randomized

Interventional model

Crossover Assignment

Masking

Triple Blind

55 participants in 2 patient groups, including a placebo group

Active Treatment
Active Comparator group
Description:
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
Treatment:
Behavioral: Neuropsychological tests
Behavioral: Cognitive functioning tests
Other: MRI Scan - Arterial Spin Labelling
Drug: Tadalafil
Control
Placebo Comparator group
Description:
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
Treatment:
Drug: Placebo
Behavioral: Neuropsychological tests
Behavioral: Cognitive functioning tests
Other: MRI Scan - Arterial Spin Labelling

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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