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

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

Study Overview

• Status: Completed
• Conditions: Dementia, Vascular
• Intervention / Treatment: Drug: Tadalafil; Behavioral: Cognitive functioning tests; Behavioral: Neuropsychological tests; Other: MRI Scan - Arterial Spin Labelling; Drug: Placebo

Detailed 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

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SW17 0QT
    • St George's Healthcare NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

   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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: Tadalafil; single dose, 20 mg capsule p.o.; Other Names: Cialis; Behavioral: 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; Other Names: TOPF, NIHSS, MoCA,; 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; Other Names: CANTAB, BMIPB, RBANS subtest; Other: 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
Placebo Comparator: 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	Behavioral: 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; Other Names: TOPF, NIHSS, MoCA,; 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; Other Names: CANTAB, BMIPB, RBANS subtest; Other: 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; Drug: Placebo; single dose, matching capsule p.o.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
change in deep brain blood flow as measured by MRI-Arterial Spin Labelling	3-5 hours following IMP dosing

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in regional CBF in cortical grey matter areas Plasma [drug concentration] dependence of deep CBF as measured by MRI ASL Changes in neuropsychological parameters including attention in Neuro attention and cognitive speed	3-5 hours following IMP dosing

Collaborators and Investigators

• Sponsor: St George's, University of London
• Collaborators: University of Copenhagen; Alzheimer's Drug Discovery Foundation; Alzheimer's Society; St George's University Hospitals NHS Foundation Trust; University of Glasgow
• Investigators: Principal Investigator: Jeremy Dr Isaacs, MRCP PhD, St George's University Hospitals NHS Foundation Trust

Publications and helpful links

General Publications

• Binnie LR, Pauls MMH, Benjamin P, Dhillon MK, Betteridge S, Clarke B, Ghatala R, Hainsworth FAH, Howe FA, Khan U, Kruuse C, Madigan JB, Moynihan B, Patel B, Pereira AC, Rostrup E, Shtaya ABY, Spilling CA, Trippier S, Williams R, Isaacs JD, Barrick TR, Hainsworth AH. Test-retest reliability of arterial spin labelling for cerebral blood flow in older adults with small vessel disease. Transl Stroke Res. 2022 Aug;13(4):583-594. doi: 10.1007/s12975-021-00983-5. Epub 2022 Jan 26.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): January 25, 2018
• Study Completion (Actual): January 25, 2018

Study Registration Dates

• First Submitted: May 18, 2015
• First Submitted That Met QC Criteria: May 20, 2015
• First Posted (Estimate): May 21, 2015

Study Record Updates

• Last Update Posted (Actual): October 27, 2022
• Last Update Submitted That Met QC Criteria: October 25, 2022
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Vascular cognitive impairment
• Additional Relevant MeSH Terms: Mental Disorders; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Neurocognitive Disorders; Dementia; Intracranial Arterial Diseases; Intracranial Arteriosclerosis; Leukoencephalopathies; Dementia, Vascular; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: 14.0189; 2015-001235-20 (EudraCT Number); 15/LO/0714 (Other Identifier: Research Ethics Committee (REC)); 20140901 (ADDF)