Efficacy of nitric oxide in stroke
| ISRCTN | ISRCTN99414122 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN99414122 |
| EudraCT/CTIS number | 2004-003870-27 |
| ClinicalTrials.gov number | NCT00989716 |
| Secondary identifying numbers | N/A |
- Submission date
- 12/11/2002
- Registration date
- 12/11/2002
- Last edited
- 31/07/2017
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English summary of protocol
Background and study aims
Lowering blood pressure reduces the risk of further strokes in patients who have already had one or more strokes. High blood pressure is common in the first hours and days following a stroke and increases the risk of the patient not recovering fully and being left with some disability. Lowering blood pressure in the first hours and days after stroke with medications might help patients to recover. Although at present we routinely treat high blood pressure long term after a stroke, we do not do so immediately after the stroke. We aim to find out what effect glyceryl trinitrate (or GTN) has on how well people recover from strokes. GTN is a tried and tested drug used in other medical conditions that acts quickly to relax blood vessels and lower blood pressure. The data will help doctors decide whether blood pressure lowering treatments like GTN can be used in patients with acute stroke to improve recovery. We also aim to assess whether or not usual blood pressure medicines should be stopped or continued for 7 days after a stroke.
Who can participate?
Adult (age > 18 years) patients presenting with an acute stroke syndrome with residual motor weakness within 48 hours of onset
What does the study involve?
Patients are randomly allocated to receive either transdermal glyceryl trinitrate patches (GTN) or no GTN for 7 days. Patients who are already receiving blood pressure lowering treatments are also randomly allocated to either continue or stop this treatment for 7 days.
What are the possible benefits and risks of participating?
Participation in the study may reduce the symptoms of the stroke or improve long-term recovery. The information received from patients involvement may benefit other people who may have a stroke in the future. All drugs have the possibility of side effects. The side effects from GTN are generally mild. They can include headache, low blood pressure and dizziness.
Where is the study run from?
The University of Nottingham (UK)
When is the study starting and how long is it expected to run for?
January 2004 to October 2013
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Prof. Philip Bath
enos@nottingham.ac.uk
Contact information
Scientific
Stroke, Division of Clinical Neuroscience, School of Medicine
University of Nottingham
City Hospital Campus
Nottingham
NG5 1PB
United Kingdom
| Phone | +44 (0)115 823 1768 |
|---|---|
| enos@nottingham.ac.uk |
Study information
| Study design | Prospective international multicentre randomised parallel-group double-blind placebo-controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Patient information can be found at: http://www.enos.ac.uk/enospisv211.pdf |
| Scientific title | A prospective, collaborative, international, multicentre, randomised, parallel-group, single and outcome blinded, controlled, factorial trial to investigate the safety and efficacy of treatment with transdermal glyceryl trinitrate, a nitric oxide donor, and of continuing or stopping temporarily pre-stroke antihypertensive therapy, in patients with acute stroke |
| Study acronym | ENOS |
| Study objectives | Three-quarters of patients are hypertensive at the presentation of acute stroke while a high blood pressure is independently associated with a poor outcome. No large trials have specifically assessed whether blood pressure should be actively altered during the acute phase of stroke although outcome was worse in some trials of calcium channel blockers and beta receptor antagonists, probably through negative effects on cerebral blood perfusion and cardiac output. However, small studies involving drugs from other antihypertensive classes, including nitric oxide donors, suggest they may reduce blood pressure without reducing cerebral blood flow. Similarly, no studies have assessed whether prior anti-hypertensive medication should be stopped or continued. A definitive trial is now required to: 1. Assess the balance of risk and benefit of lowering blood pressure immediately after ischaemic and haemorrhagic stroke. 2. Assess whether prior antihypertensive therapy should be continued or stopped temporarily after stroke. Protocol can be found at: http://www.enos.ac.uk/enosprotocolv15.pdf Further reading (added 28/01/2010): 1. The NeuroGrid stroke exemplar clinical trial protocol. Wardlaw JM et al. International Journal of Stroke 2007;2:63-69 http://www.ncbi.nlm.nih.gov/pubmed/18705995 2. Effect of nitric oxide donors on blood pressure and pulse pressure in acute and subacute stroke. Gray LJ et al. International Journal of Stroke 2007;2:63-69 http://www.ncbi.nlm.nih.gov/pubmed/17904083 3. Management of blood pressure in acute stroke. Phillips at al. Canadian J Neurological Sciences 2002;29;404 http://www.ncbi.nlm.nih.gov/pubmed/12463498 4. ENOS Efficacy of Nitric Oxide in Stroke Trial. Stroke Center Stroke Trials Registry (2002) http://www.strokecenter.org/trials/TrialDetail.aspx?tid=103 |
| Ethics approval(s) | Trent Regional Ethics Committee (REC) and the National Research Ethics Service (NRES), 03/09/2001, ref: MREC/01/4/046 |
| Health condition(s) or problem(s) studied | Acute stroke |
| Intervention | 1. Glyceryl trinitrate (transdermal) 2. Continue/temporarily stop prior anti-hypertensive therapy |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Glyceryl trinitrate |
| Primary outcome measure | Death and dependency (Rankin score more than two). |
| Secondary outcome measures | 1. Events by 7 days - recurrent stroke, symptomatic deep vein thrombosis, symptomatic pulmonary embolism, blood pressure daily between 1 and 7 days 2. Hospital events - length of stay in hospital, discharge disposition (death, institution or home) 3. Outcome at 90 days - Barthel Index (less than 60, including death), Barthel Index more than 95/100 at three months (good outcome), quality of life (EuroQol), abbreviated mental test score 4. Safety measures - death at 7 and 90 days, symptomatic intracranial haemorrhage at 7 days, major extracranial haemorrhage at 10 days |
| Overall study start date | 01/01/2004 |
| Completion date | 31/10/2013 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | 3500+ |
| Key inclusion criteria | 1. Patients with acute ischaemic or haemorrhagic stroke within 48 hours 2. Systolic blood pressure 140-220 mmHg |
| Key exclusion criteria | 1. Unconscious (Glasgow Coma Scale less than eight) 2. Definite need for nitrate therapy: concurrent myocardial infarction, unstable angina, left ventricular failure 3. Dehydration 4. Contraindication to nitrate therapy: hypersensitivity to nitrates, hypovolaemia, hypertrophic obstructive cardiomyopathy, aortic stenosis, cardiac tamponade, constrictive pericarditis, mitral stenosis, marked anaemia, closed-angle glaucoma, sildenafil (Viagra) within previous 24 hours 5. Systolic blood pressure less than 140 mmHg or more than 220 mmHg 6. Patients expected to require surgical intervention (e.g. clot evacuation, carotid endarterectomy) during the treatment or follow-up period 7. Refusal to consent 8. Patient dependent on others prior to stroke (e.g. Rankin score more than three) 9. Known intracerebral pathology other than ischaemic stroke, e.g. subarachnoid haemorrhage, brain tumour, cerebral abscess 10. Other serious condition which is likely to prevent outcome assessment, e.g. advanced cancer 11. Involvement in a trial of another experimental intervention (drug or surgery) for acute stroke 12. Not available for follow-up, e.g. no fixed address, overseas visitor 13. Females of childbearing potential, pregnancy or breastfeeding |
| Date of first enrolment | 01/01/2004 |
| Date of final enrolment | 31/10/2013 |
Locations
Countries of recruitment
- Australia
- Canada
- China
- Denmark
- Egypt
- England
- Georgia
- Greece
- Hong Kong
- India
- Ireland
- Italy
- Malaysia
- New Zealand
- Norway
- Philippines
- Poland
- Romania
- Singapore
- Spain
- Sri Lanka
- Sweden
- Türkiye
- United Kingdom
Study participating centre
NG5 1PB
United Kingdom
Sponsor information
University/education
University Park
Nottingham
NG7 2RD
England
United Kingdom
| Website | http://www.nottingham.ac.uk/SCS/Divisions/Stroke/index.aspx |
|---|---|
"ROR" |
https://ror.org/01ee9ar58 |
Funders
Funder type
Charity
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
No information available
Private sector organisation / Trusts, charities, foundations (both public and private)
- Location
- United Kingdom
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
No information available
Private sector organisation / Associations and societies (private and public)
- Location
- United Kingdom
Private sector organisation / Universities (academic only)
- Location
- United Kingdom
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Abstract results | 01/01/2005 | No | No | ||
| Protocol article | protocol | 01/11/2006 | Yes | No | |
| Interim results article | interim results | 01/02/2009 | Yes | No | |
| Results article | results | 01/03/2013 | Yes | No | |
| Results article | results | 01/12/2013 | Yes | No | |
| Statistical Analysis Plan | statistical analysis plan | 01/04/2014 | No | No | |
| Other publications | patient baseline characteristics | 01/08/2014 | Yes | No | |
| Results article | results | 14/02/2015 | Yes | No | |
| Results article | results | 01/11/2015 | Yes | No | |
| Results article | results | 01/01/2016 | Yes | No | |
| Results article | results | 01/12/2017 | Yes | No |
Editorial Notes
31/07/2017: Publication reference added.
19/06/2014: The following changes were made to the trial record:
1. The scientific title was added.
2. Denmark, Republic of Ireland, Georgia, Greece, Norway, Sweden and Turkey were added to the countries of recruitment and Belgium and Saudi Arabia were removed.
3. The target number of participants was changed from 5000 to 3500+.
01/02/2010: The overall trial end date was changed from 31/10/2011 to 31/10/2013.
28/01/2010: The following countries of recruitment were added: Egypt, India, Malaysia, Romania, Saudi Arabia, Spain, and Sri Lanka.
