Oxford Haemodynamic Adaptation to Reduce Pulsatility Trial (OxHARP)

Inclusion Criteria:

• Participant is willing and able to give informed consent for participation in the study.
• Male or Female, aged 18 years or above.
• Can record MCA waveform on at least one side ('useable TCD window')
• Non-disabling, ischaemic stroke or TIA, >1 month prior to randomisation, of either cryptogenic or lacunar aetiology, confirmed clinically or on brain imaging
• White matter hyperintensities on MRI (Fazekas scale) or CT (Blennow scale) consistent with cerebral small vessel disease
• Age below 60 MRI Fazekas score 1 to 3 (max 2 points in periventricular or deep score) or CT Blennow score 1 to 3 (max 2 points in periventricular or deep score)
• Age above 60 MRI Fazekas score 1 to 4 (max 2 points in periventricular or deep score) or CT Blennow score 1 to 4 (max 2 points in periventricular or deep score)

Exclusion Criteria:

• Pregnant or breastfeeding women, women of childbearing age not taking contraception.
• Other major neurological or psychiatric conditions affecting the brain and interfering with the study design (e.g. multiple sclerosis)

• Other causes of stroke such as

  • ≥50% luminal stenosis (NASCET) in large arteries supplying the infarct area
  • major-risk cardioembolic source of embolism (permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumours, mitral stenosis, recent (<4 weeks) myocardial infarction, left ventricular ejection fraction less than 30%, valvular vegetations, or infective endocarditis)
  • other specific causes of stroke (e.g. arteritis, dissection, drug misuse)
• Large vessel occlusion on MRA or CTA (carotid, basilar or MCA)
• Modified Rankin Score >3
• Unable to swallow
• Renal impairment (eGFR <35ml/min)
• Significant biochemical abnormalities (sodium <130, K+ <2.5 or >5.5, LFTs >3 x upper limit of normal range)
• Life expectancy <2 years

• Contraindication to active agents

  • Concurrent use of alphablocker
  • Regular use of nitrate (ISMN, GTN, other)
  • Heart failure (NYHA 2-4)
  • Severe aortic stenosis
  • Bilateral renal artery stenosis
  • Uncontrolled arrhythmias
  • Previous priapism
  • Anatomical deformation of the penis
  • Recent myocardial infarction (within 6 months)
  • Unstable angina
  • History of non-arteritic ischaemic optic neuropathy
  • Hypotension: BP <90/60
  • Haemodynamically significant aortic / mitral valve disease
  • Sickle cell disease, myeloma, leukaemia
  • Uncontrolled hypertension (BP >180/110 despite treatment with 3 antihypertensives)
• Scheduled elective surgery or other procedures requiring general anaesthesia during the study.
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study or the participant's ability to participate in the study.
• Participants who have participated in another research study involving an investigational product in the past 12 weeks.
• Use of an anticoagulant (warfarin, dabigatran, rivaroxaban etc) or more than one antiplatelet drug.
• Predisposition to intracerebral haemorrhage (previous ICH, likely cerebral amyloid angiopathy) or intraocular haemorrhage (uncontrolled diabetic retinopathy or neovascularisation)
• Allergy to constituents of medications or components of placebo / overencapsulation
• Use of CYP inducers that interact with study medications (ketoconazole, erythromycin).

Exclusion criteria specific for MRI substudy

• Not able to transfer to MRI scanner
• Active respiratory illness (such as moderate to severe asthma or COPD) such that they are unable to tolerate MRI or unable to lie flat
• Claustrophobia
• Contraindication to MRI scan (pacemaker, aneurysm clip etc)