Small Vessel Cerebrovascular DiseasePhase 2OxHARPNCT03855332
Oxford Haemodynamic Adaptation to Reduce Pulsatility Trial
A Phase 2 study testing Sildenafil and Cilostazol in people with Small Vessel Cerebrovascular Disease, run by University of Oxford at 1 site in United Kingdom.
Trial summary
Chronic damage to small blood vessels deep in the brain is seen in half of patients over the age of 60 and almost all patients over the age of 80, and is responsible for up to a third of strokes and almost half of patients with dementia. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Small Vessel Cerebrovascular Disease
- What is being tested?
- Sildenafil and Cilostazol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 75 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 11 Jul 2019to 6 Jan 2023
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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)
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- 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).
- 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)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Oxford Haemodynamic Adaptation to Reduce Pulsatility: Randomised, Placebo-controlled, Double-blind Crossover Trial of Effects of Sildenafil on Cerebral Arterial Pulsatility in Patients With Cryptogenic or Lacunar Stroke and Small Vessel Disease
Chronic damage to small blood vessels deep in the brain is seen in half of patients over the age of 60 and almost all patients over the age of 80, and is responsible for up to a third of strokes and almost half of patients with dementia. However, there is limited evidence for how small vessel disease develops and no specific treatment. One potential explanation is that greater pulsations in blood pressure are transmitted to the brain through stiff blood vessels, resulting in increased pressure hitting the brain each time the heart beats and reduced blood flow between heart beats.
Sildenafil is used to open up blood vessels (a vasodilator) in patients with erectile difficulties or poor blood supply to the lungs. This trial will test sildenafil (50mg, thrice daily) against placebo and a similar drug (cilostazol 100mg, twice daily) in 75 patients with previous stroke or mini-stroke and small vessel disease, given in random order to every participant for 3 weeks each. It will primarily assess changes in pulsations of blood flow to the brain on each tablet, measured with an ultrasound scanner (transcranial ultrasound). To understand why any changes occur, we will also measure the stiffness of arteries, the blood pressure at the heart and how much blood vessels in the brain open up when participants breathe air with added carbon dioxide (6%), using ultrasound in all participants and on MRI brain scans in 30 patients.
This study will test whether a vasodilator used in other conditions with a good safety profile can reduce pulsations in blood flow to the brain, to assess whether it is a good candidate drug to reduce the progression of small vessel disease in future clinical trials. This would be the first effective treatment for a condition associated with a very high burden of disability.
- Conditions
- Small Vessel Cerebrovascular Disease
- Being tested
- Sildenafil, Cilostazol, Placebo
- Medical subject headings
- Cerebral Small Vessel Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SildenafilDrug
See above
CilostazolDrug
See above
PlaceboDrug
Overencapsulated placebo
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | All participants will undergo three phases in random order:
The placebo phase will include overencapsulated placebo, matched to overencapsulated active agents, 2 tablets 3 times daily Receives: Drug: Placebo |
| Sildenafil | Experimental | 25mg three times daily, overencapsulated tablet, increased after 1 week to 50mg three times daily Receives: Drug: Sildenafil |
| Cilostazol | Active comparator | 50mg bd, overencapsulated tablet (with midday placebo), increased after 1 week to 100mg bd (with midday placebo) Receives: Drug: Cilostazol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Middle cerebral arterial pulsatility index
Difference in Gosling's pulsatility index after three weeks treatment with sildenafil versus placebo, in 75 patients
Measured: 3 weeks
Secondary outcomes (1)
Percentage increase in MCA velocity on 6% CO2 vs medical air
- Difference in cerebrovascular reactivity after 3 weeks of treatment with sildenafil versus placebo in 75 patients: cereborovascular reactivity calculated by the percentage increase in mean MCA velocity whilst breathing 6% CO2 compared to breathing medical air.
- Non-inferiority of 3 weeks of treatment with cilostazol 100mg bd compared to sildenafil 50mg tds for difference in Gosling's pulsatility index and cerebrovascular reactivity to 6% CO2.
Measured: 3 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Feb 2019
- Study start11 Jul 2019
- Primary completion6 Dec 2022
- Study completion6 Jan 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Small Vessel Cerebrovascular DiseaseStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Randomised, double-blind, placebo and active controlled, crossover design
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 75 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- Wellcome Trust
- Responsible party
- Sponsor
- Investigators
- Dr A Webb, DPhil, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03855332
- Sponsor's protocol ID
- 13891
- Other IDs
- 206589/Z/17/Z
- Acronym
- OxHARP
- Status last verified
- May 2022
- First submitted
- 21 Feb 2019
- Last updated
- 19 Nov 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: This will be determined on specific request
Publications
Webb AJ, Feakins K, Lawson A, Stewart C, Thomas J, Llwyd O. White matter hyperintensities are independently associated with systemic vascular aging and cerebrovascular dysfunction. Int J Stroke. 2025 Jun;20(5):581-589. doi: 10.1177/17474930241306987. Epub 2025 Jan 3.
PubMed 39614707Webb AJS, Birks JS, Feakins KA, Lawson A, Dawson J, Rothman AMK, Werring DJ, Llwyd O, Stewart CR, Thomas J. Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial. Circ Res. 2024 Jul 5;135(2):320-331. doi: 10.1161/CIRCRESAHA.124.324327. Epub 2024 Jun 4.
PubMed 38832504Webb A, Werring D, Dawson J, Rothman A, Lawson A, Wartolowska K. Design of a randomised, double-blind, crossover, placebo-controlled trial of effects of sildenafil on cerebrovascular function in small vessel disease: Oxford haemodynamic adaptation to reduce pulsatility trial (OxHARP). Eur Stroke J. 2021 Sep;6(3):283-290. doi: 10.1177/23969873211026698. Epub 2021 Jun 23.
PubMed 34746425