Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Oxford Haemodynamic Adaptation to Reduce Pulsatility Trial (OxHARP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03855332
Recruitment Status : Recruiting
First Posted : February 26, 2019
Last Update Posted : August 2, 2019
Sponsor:
Collaborator:
Wellcome Trust
Information provided by (Responsible Party):
University of Oxford

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.


Condition or disease Intervention/treatment Phase
Small Vessel Cerebrovascular Disease Drug: Sildenafil Drug: Cilostazol Drug: Placebo Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
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
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
Actual Study Start Date : July 11, 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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

Drug: Placebo
Overencapsulated placebo

Experimental: Sildenafil
25mg three times daily, overencapsulated tablet, increased after 1 week to 50mg three times daily
Drug: Sildenafil
See above

Active Comparator: Cilostazol
50mg bd, overencapsulated tablet (with midday placebo), increased after 1 week to 100mg bd (with midday placebo)
Drug: Cilostazol
See above




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.


Other Outcome Measures:
  1. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03855332


Contacts
Layout table for location contacts
Contact: Dr A Webb, DPhil +441865231601 alastair.webb@ndcn.ox.ac.uk

Locations
Layout table for location information
United Kingdom
University of Oxford Recruiting
Oxford, Oxon, United Kingdom, OX39DU
Contact: Alastair Webb, DPhil    +441865231601    alastair.webb@ndcn.ox.ac.uk   
Sponsors and Collaborators
University of Oxford
Wellcome Trust
Investigators
Layout table for investigator information
Principal Investigator: Dr A Webb, DPhil University of Oxford

Layout table for additonal information
Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT03855332     History of Changes
Other Study ID Numbers: 13891
206589/Z/17/Z ( Other Grant/Funding Number: Wellcome Trust )
First Posted: February 26, 2019    Key Record Dates
Last Update Posted: August 2, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: This will be determined on specific request

Layout table for additional information
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
Additional relevant MeSH terms:
Layout table for MeSH terms
Cerebrovascular Disorders
Cerebral Small Vessel Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Cilostazol
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Platelet Aggregation Inhibitors
Neuroprotective Agents
Protective Agents
Phosphodiesterase 3 Inhibitors