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.
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.
- Placebo Drug
Intervention Desc: 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. ARM 1: Kind: Experimental Label: Control Description: Placebo Capsule. MRI of cerebrum pre dose. Transcranial Doppler, endothelial response with EndoPAT2000, and endothelial biomarkers (pre and post dose).
- Tadalafil Drug
Other Names: Cialis Intervention Desc: 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. ARM 1: Kind: Experimental Label: Active Treatment Description: Tadalafil 20 mg Capsule. MRI of cerebrum pre dose. Transcranial Doppler, endothelial response with EndoPAT2000, and endothelial biomarkers (pre and post dose).
- Allocation: Randomized
- Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
- Purpose: Treatment
- Endpoint: Pharmacodynamics Study
- Intervention: Crossover Assignment
|Type||Measure||Time Frame||Safety Issue|
|Primary||Difference in Blood flow velocity change in middel cerebral artery (MCA) between placebo and tadalafil||Measurement before and up to three hours after intake of tadalafil/placebo.||No|
|Secondary||Endothelial function/response||Measurement before and three hours after intake of tadalafil/placebo.||No|
|Secondary||Endothelial function/response biomarkers in blood||Blood samples before and 3,5-4 hours after intake of tadalafil/placebo.||No|
|Secondary||Changes in endothelial response||Measurement before and three hours after intake of tadalafil/placebo.||No|
|Secondary||Changes in endothelial biomarkers in blood||Blood samples before and 3,5-4 hours after intake of tadalafil/placebo.||No|
|Primary||Difference in cortical brain oxygenation between placebo and tadalafil||Measurement before and up to three hours after intake of tadalafil/placebo.|
- Christina Kruuse Lead