Oxford Haemodynamic Adaptation to Reduce Pulsatility Trial (OxHARP)

• ClinicalTrials.gov Identifier: NCT03855332
• Recruitment Status: Recruiting
• First Posted: February 26, 2019
• Last Update Posted: August 2, 2019
• Sponsor: University of Oxford
• Collaborator: Wellcome Trust
• Information provided by (Responsible Party): University of Oxford

Tracking Information

• First Submitted Date: February 21, 2019
• First Posted Date: February 26, 2019
• Last Update Posted Date: August 2, 2019
• Actual Study Start Date: July 11, 2019
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 25, 2019)

Middle cerebral arterial pulsatility index [ Time Frame: 3 weeks ]

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

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT03855332 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: February 25, 2019)

Percentage increase in MCA velocity on 6% CO2 vs medical air [ Time Frame: 3 weeks ]

1. 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.
2. 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.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: February 25, 2019)

Reactivity of BOLD signal on MRI to 6% CO2 challenge [ Time Frame: 3 weeks ]

Difference in cerebrovascular reactivity after 3 weeks of treatment with sildenafil versus placebo in 30 patients: cerebrovascular reactivity calculated by the percentage increase in BOLD signal on MRI whilst breathing 6% CO2 compared to breathing medical air.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Oxford Haemodynamic Adaptation to Reduce Pulsatility Trial
• 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

Randomised, double-blind, placebo and active controlled, crossover design

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention

• Condition: Small Vessel Cerebrovascular Disease

Intervention

• Drug: Sildenafil
  See above
• Drug: Cilostazol
  See above
• Drug: Placebo
  Overencapsulated placebo

Study Arms

• Placebo Comparator: Placebo

  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

  Intervention: Drug: Placebo
• Experimental: Sildenafil
  25mg three times daily, overencapsulated tablet, increased after 1 week to 50mg three times daily
  Intervention: Drug: Sildenafil
• Active Comparator: Cilostazol
  50mg bd, overencapsulated tablet (with midday placebo), increased after 1 week to 100mg bd (with midday placebo)
  Intervention: Drug: Cilostazol

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 25, 2019): 75
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2021
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Dr A Webb, DPhil; +441865231601; alastair.webb@ndcn.ox.ac.uk

• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT03855332
• Other Study ID Numbers: 13891; 206589/Z/17/Z ( Other Grant/Funding Number: Wellcome Trust )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: This will be determined on specific request

• Responsible Party: University of Oxford
• Study Sponsor: University of Oxford
• Collaborators: Wellcome Trust

Investigators

• Principal Investigator: Dr A Webb, DPhil; University of Oxford

• PRS Account: University of Oxford
• Verification Date: February 2019