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Effect of Tadalafil on Cerebral Large Arteries in Stroke (ETLAS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02801032
Recruitment Status : Completed
First Posted : June 15, 2016
Last Update Posted : August 22, 2017
Sponsor:
Information provided by (Responsible Party):
Christina Kruuse, Herlev Hospital

Brief Summary:
In a double blind placebo-controlled cross-over study the effect of tadalafil on blood flow velocity in the large arteries of the brain, cortical brain oxygenation, peripheral endothelial function, and endothelial biomarkers will be tested in patients with lacunar stroke caused by cerebral small vessel disease.

Condition or disease Intervention/treatment Phase
Stroke, Lacunar Cerebral Small Vessel Diseases Drug: Tadalafil Drug: Placebo Phase 2

Detailed Description:

Stroke frequently causes death and decreased function in the everyday life, and the disease has a great human and economic impact. Cerebral small vessel disease (SVD) is the underlying cause of 25 % of all ischemic cerebral strokes and it can further lead to vascular cognitive impairment (VCI), disability and in some cases vascular dementia (VaD). It is well known that cerebral blood flow (CBF) is reduced in VCI. To be able to improve the blood flow in the vasculature of white and gray matter is therefore desirable in slowing the pathology of VCI.

The nitric oxide-cGMP vasodilator pathways has been shown to be impaired in endothelial dysfunction which is seen in SVD.This study targets this well-established mechanism of action by use of a compound selectively inhibiting the breakdown of cGMP, the PDE5 inhibitor tadalafil.

The overall hypothesis is that chronic PDE5 inhibition with tadalafil will lessen the severity and progression of vascular brain lesions via augmentation of cerebral blood flow in the deep brain areas. The specific primary hypothesis for the current project is that PDE5 inhibition with a single dose of tadalafil (Cialis®) will, in contrast to placebo, temporarily change the blood flow in the large blood vessels in the brain and change cortical brain oxygenation in patients with cerebral small vessel disease measured with Transcranial Doppler and near-infrared spectroscopy (NIRS). The secondary hypothesis is that tadalafil will improve the peripheral endothelial function measured as improved blood vessel response in the fingers after a brief occlusion of the arm's blood supply measured with EndoPAT2000. In addition there will be a change of endothelial function biomarkers in the blood after a single dose of tadalafil, and these changes are consistent with the measured peripheral and central blood vessel function.

In regulation of cerebral artery flow and neuronal signalling nitric oxide (NO) and cGMP act as key molecules. In animal models, selective inhibitors of the cGMP degrading PDE5, sildenafil and tadalafil, have been reported to improve the associated symptoms of endothelial dysfunction and stroke recovery. Pre-clinical studies support a CBF-enhancing action of PDE5 inhibitors 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®; Eli Lilly) is widely prescribed for erectile dysfunction in men. It is also registered for regular daily use at a dose of 40 mg for pulmonary hypertension and 5 mg for benign prostatic hyperplasia. The side effects of tadalafil is well-known and the medicine is usually well tolerated. Tadalafil was chosen over other PDE5 inhibitors (such as sildenafil, Viagra®) due to it's potency, plasma half-life, selectivity for PDE5, and documented brain penetration.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effect of Tadalafil on Cerebral Large Arteries in Stroke Patients
Actual Study Start Date : November 29, 2016
Actual Primary Completion Date : August 4, 2017
Actual Study Completion Date : August 4, 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Tadalafil

Arm Intervention/treatment
Active Comparator: Active Treatment
Tadalafil 20 mg Capsule. MRI of cerebrum pre dose. Transcranial Doppler, near-infrared spectroscopy (NIRS), endothelial response with EndoPAT2000, and endothelial biomarkers (pre and post dose).
Drug: Tadalafil

Single dose, 20 mg capsule p.o. minimum one week apart from placebo.

MRI of cerebrum before the first trial day.

Transcranial Doppler to measure blood flow velocity in MCA bilaterally before and after intervention.

Near-infrared spectroscopy (NIRS) to measure cortical brain oxygenation before and after intervention.

EndoPAT2000 to estimate endothelial function before and after intervention.

Endothelial biomarkers in blood samples before and after intervention.

Other Name: Cialis

Placebo Comparator: Control
Placebo Capsule. MRI of cerebrum pre dose. Transcranial Doppler, near-infrared spectroscopy (NIRS), endothelial response with EndoPAT2000, and endothelial biomarkers (pre and post dose).
Drug: Placebo

Single dose, matching capsule p.o. minimum one week apart from active treatment.

MRI of cerebrum before the first trial day.

Transcranial Doppler to measure blood flow velocity in MCA bilaterally before and after intervention.

Near-infrared spectroscopy (NIRS) to measure cortical brain oxygenation before and after intervention.

EndoPAT2000 to estimate endothelial function before and after intervention.

Endothelial biomarkers in blood samples before and after intervention.





Primary Outcome Measures :
  1. Difference in Blood flow velocity change in middel cerebral artery (MCA) between placebo and tadalafil [ Time Frame: Measurement before and up to three hours after intake of tadalafil/placebo. ]
    Change in Blood flow velocity in middel cerebral artery (MCA) will be measured with transcranial doppler (TCD) before and up to three hours after intake of tadalafil/placebo.

  2. Difference in cortical brain oxygenation between placebo and tadalafil [ Time Frame: Measurement before and up to three hours after intake of tadalafil/placebo. ]
    Cortical brain oxygenation will be measured with near-infrared spectroscopy (NIRS) before and up to three hours after intake of tadalafil/placebo.


Secondary Outcome Measures :
  1. Changes in endothelial response [ Time Frame: Measurement before and three hours after intake of tadalafil/placebo. ]
    Measurement of endothelial response by EndoPAT2000 before and three hours after intake of tadalafil/placebo.

  2. Changes in endothelial biomarkers in blood [ Time Frame: Blood samples before and 3,5-4 hours after intake of tadalafil/placebo. ]
    Blood samples to measure changes in endothelial biomarkers (eg. e-selectin, VCAM, ICAM, endothelin, ADMA, miRNA) before and 3,5-4 hours after intake of tadalafil/placebo.



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

    1. lacunar stroke syndrome with symptoms lasting >24 hours occurring at least 5 months previously; OR
    2. transient ischemic attack (TIA) lasting < 24 hours with limb weakness, hemi-sensory loss or dysarthria at least 5 months previously AND with MR DWI performed acutely showing lacunar infarction, OR if MRI is not performed within ten days of TIA, a lacunar infarction in an anatomically appropriate position is demonstrated on a subsequent MRI.
  3. Age ≥ 50 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. Pregnancy or nursing
  3. Cortical infarction (>1.5 cm maximum diameter)
  4. Systolic BP < 90 and/or diastolic BP < 50
  5. eGFR < 30 ml/min/1,73m2
  6. Severe hepatic impairment
  7. History of Lactose intolerance
  8. Concomitant use of PDE5 inhibitors e.g. sildenafil, tadalafil, vardenafil
  9. Patients receiving nicorandil and nitrates e.g. isosorbide mononitrate, isosorbide dinitrate, glyceryl trinitrate
  10. Body weight > 130kg
  11. Uncontrolled cardiac failure
  12. Persistent or paroxysmal atrial fibrillation
  13. History of "sick sinus syndrome" or other supraventricular cardiac conduction conditions such as sinoatrial or atrioventricular block
  14. Uncontrolled COPD
  15. Stroke or TIA within the last 5 months.
  16. MRI not tolerated or contraindicated: MRI exclusion criteria: Participant has a cardiac pacemaker; recent surgery; vascular clips; metal implants or joint replacements that are not compatible with MRI; have had metal fragments in their eyes; has ever worked on a lathe; has shrapnel from a war injury; possibility of pregnancy
  17. Known monogenic causes of stroke i.e. CADASIL
  18. The patient does not wish to know important results from MRI
  19. Unable to provide informed consent
  20. Not possible to localise a. cerebri media bilaterally on inclusion day with Transcranial Doppler

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02801032


Locations
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Denmark
Department of Neurology, Herlev-Gentofte Hospital
Herlev, Denmark, 2730
Sponsors and Collaborators
Christina Kruuse
Investigators
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Principal Investigator: Christina R Kruuse, MD, PhD Consultant Neurologist, Dept Neurology, Herlev Hospital

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Responsible Party: Christina Kruuse, MD, PhD, DMSc, Consultant Neurologist, Associate Professor, Herlev Hospital
ClinicalTrials.gov Identifier: NCT02801032    
Other Study ID Numbers: H-16020836
2016-000896-26 ( EudraCT Number )
First Posted: June 15, 2016    Key Record Dates
Last Update Posted: August 22, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Stroke
Cerebral Small Vessel Diseases
Stroke, Lacunar
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Tadalafil
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents