Oxford Haemodynamic Adaptation to Reduce Pulsatility Trial

NCT03855332 | Completed Phase 2 DMC

• 2 other identifiers: 13891206589/Z/17/Z
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief 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. 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

Outcome Measures

Primary Outcomes (1)

• Middle cerebral arterial pulsatility index

  Difference in Gosling's pulsatility index after three weeks treatment with sildenafil versus placebo, in 75 patients

  3 weeks

Secondary Outcomes (1)

• Percentage increase in MCA velocity on 6% CO2 vs medical air

  3 weeks

Other Outcomes (1)

• Reactivity of BOLD signal on MRI to 6% CO2 challenge

  3 weeks

Study Arms (3)

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

Drug: Placebo

Sildenafil

EXPERIMENTAL

25mg three times daily, overencapsulated tablet, increased after 1 week to 50mg three times daily

Drug: Sildenafil

Cilostazol

ACTIVE COMPARATOR

50mg bd, overencapsulated tablet (with midday placebo), increased after 1 week to 100mg bd (with midday placebo)

Drug: Cilostazol

Interventions

Sildenafil DRUG

See above

Sildenafil

Cilostazol DRUG

See above

Cilostazol

Placebo DRUG

Overencapsulated placebo

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Oxford: lead
• Wellcome Trust: collaborator

Study Sites (1)

University of Oxford

Oxford, Oxon, OX39DU, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 39614707 DERIVED

• Webb 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.

  PMID: 38832504 DERIVED

• Webb 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.

  PMID: 34746425 DERIVED

MeSH Terms

Conditions

Cerebral Small Vessel Diseases

Interventions

Sildenafil Citrate; Cilostazol

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tetrazoles; Azoles; Quinolines

Study Officials

• Dr A Webb, DPhil

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomised, double-blind, placebo and active controlled, crossover design

Study Record Dates

• First Submitted: February 21, 2019
• First Posted: February 26, 2019
• Study Start: July 11, 2019
• Primary Completion: December 6, 2022
• Study Completion: January 6, 2023
• Last Updated: November 19, 2025

Record last verified: 2022-05

Locations

GB (1)