search
Back to results

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

Primary Purpose

Dementia, Vascular

Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Tadalafil
Placebo
Cognitive functioning tests
Neuropsychological tests
MRI Scan - Arterial Spin Labelling
Sponsored by
St George's, University of London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Dementia, Vascular focused on measuring Vascular cognitive impairment

Eligibility Criteria

55 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • St George's Healthcare NHS Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Active Treatment

Control

Arm 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

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

Outcomes

Primary Outcome Measures

change in deep brain blood flow as measured by MRI-Arterial Spin Labelling

Secondary Outcome Measures

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

Full Information

First Posted
May 18, 2015
Last Updated
October 25, 2022
Sponsor
St George's, University of London
Collaborators
Alzheimer's Drug Discovery Foundation, Alzheimer's Society, University of Copenhagen, University of Glasgow, St George's University Hospitals NHS Foundation Trust
search

1. Study Identification

Unique Protocol Identification Number
NCT02450253
Brief Title
Perfusion by Arterial Spin Labelling Following Single Dose Tadalafil in Small Vessel Disease (PASTIS) Trial
Acronym
PASTIS
Official Title
Perfusion by Arterial Spin Labelling Following Single Dose Tadalafil in Small Vessel Disease (PASTIS) Trial
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
September 2015 (undefined)
Primary Completion Date
January 25, 2018 (Actual)
Study Completion Date
January 25, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St George's, University of London
Collaborators
Alzheimer's Drug Discovery Foundation, Alzheimer's Society, University of Copenhagen, University of Glasgow, St George's University Hospitals NHS Foundation Trust

4. Oversight

Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dementia, Vascular
Keywords
Vascular cognitive impairment

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
55 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Active Treatment
Arm Type
Active Comparator
Arm 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
Arm Title
Control
Arm Type
Placebo Comparator
Arm 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
Intervention Type
Drug
Intervention Name(s)
Tadalafil
Other Intervention Name(s)
Cialis
Intervention Description
single dose, 20 mg capsule p.o.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
single dose, matching capsule p.o.
Intervention Type
Behavioral
Intervention Name(s)
Cognitive functioning tests
Other Intervention Name(s)
TOPF, NIHSS, MoCA,
Intervention Description
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
Intervention Name(s)
Neuropsychological tests
Other Intervention Name(s)
CANTAB, BMIPB, RBANS subtest
Intervention Description
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
Other
Intervention Name(s)
MRI Scan - Arterial Spin Labelling
Intervention Description
Pre and post IMP dose on 2 occasions to detect difference in blood flow in deep brain 4 MRI scans in total
Primary Outcome Measure Information:
Title
change in deep brain blood flow as measured by MRI-Arterial Spin Labelling
Time Frame
3-5 hours following IMP dosing
Secondary Outcome Measure Information:
Title
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
Time Frame
3-5 hours following IMP dosing

10. Eligibility

Sex
All
Minimum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility 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: lacunar stroke syndrome with symptoms lasting >24 hours, occurring at least 6 months previously; OR: 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: Known diagnosis of dementia Cortical infarction (>1.5 cm maximum diameter) Systolic BP <90 and/or diastolic BP < 50 Creatinine Clearance<50ml/min Severe hepatic impairment History of Lactose intolerance Concomitant use of PDE5 inhibitors e.g. sildenafil, tadalafil, vardenafil. Concomitant use of alpha-blockers e.g. alfuzosin, doxazosin, indoramin, prazosin, tamsulosin, and terazosin can all increase the risk of postural hypotension. Participants receiving nicorandil and nitrates e.g. isosorbide mononitrate, isosorbide dinitrate, glyceryl trinitrate 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeremy Dr Isaacs, MRCP PhD
Organizational Affiliation
St George's University Hospitals NHS Foundation Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
St George's Healthcare NHS Trust
City
London
ZIP/Postal Code
SW17 0QT
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
35080734
Citation
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.
Results Reference
derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs