Efficacy of Nitric Oxide in Stroke trial

ENOS

2014, October: ENOS has now been published! Many thanks to all who have contributed!

The 'Efficacy of Nitric Oxide in Stroke' (ENOS) study is a collaborative, international, multicentre, prospective, randomised, single-blind, blinded endpoint, parallel-group, controlled trial designed to test the safety and efficacy of:

transdermal glyceryl trinitrate (a nitric oxide donor) or control; and
continuing or temporarily stopping prior anti-hypertensive medication.

4,011 patients with acute ischaemic or haemorrhagic stroke were enrolled within 48 hours of the onset of stroke and treatment given for 7 days. The primary outcome is shift in death or dependency (modified Rankin Scale) determined at 90 days by observers blinded to treatment.

Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial (link to full text) The Lancet, 22 October 2014

Clinical trial could change standard treatment for stroke (link) World Pharma News (Germany), 24 October 2014

Clinical trial sheds new light on BP management during stroke treatment (link) Zee News (India), 23 October 2014

Clinical Trial may Change Standard Treatment for Stroke (link) Medindia.com (India), 23 October 2014 **NEW**

Clinical trial could change standard treatment for stroke (link) Medical News Today, 23 October 2014

Results of ENOS: "No rush to continue oral BP meds in acute stroke", 09/05/2014 (pdf) Medscape: please note an account is required but it is free to sign up

Trial results poster, 19/05/2014 (pdf)

Nerses Sanossian's blog, 07/05/2014, live from ESC 2014 clinical trials session (link)

Trial final protocol (V1.5) (pdf)

Power point presentation, V1.0 (Powerpoint, size=3.9MB)

Brief Information for patients & relatives about the trial, V1.2 (PDF file)
Full information for patients, V2.11 (PDF file, MREC approved)

ENOS trial

Enter ENOS trial site

Status

At close (14th October 2013):

Enrolled patients: 4,011 with 2,097 (52.3%) in continue vs. stop pre-stroke antihypertensive therapy

Centres who recruited one or more patients: 168

Countries who recruited one or more patients: 23 - Australia, Canada, China, Denmark, Egypt, Eire, Georgia, Greece, Hong Kong, India, Italy, Malaysia, New Zealand, Norway, Philippines, Poland, Romania, Singapore, Spain, Sri Lanka, Sweden, Turkey, UK

Continents who enrolled one or more patients: 5 - Africa, Asia, Australia-Oceania, Europe, North America

Tweets by @enostrial

Funding

Medical Research Council (UK); also as part of NeuroGRID
A*STAR (MRI sub-study) (Singapore)
BUPA Foundation (start-up phase of trial) (UK)
The Hypertension Trust (start-up phase of trial) (UK)
Reichstadt bequest (UK)
The Stroke Association (UK)
The University of Nottingham (through Information Services) (UK)

News

22nd October 2014: ENOS has now been published: Full text of The Lancet publication
14th October 2013: ENOS has now finished recruiting! Congratulations and thankyou for all your hard work!
October 2013: Congratulations to all: we have passed 4,000 recruits!
July 2013: Congratulations to everyone - trial passes 3,900 recruits!
June 2013: Data Monitoring Committee recommend trial continues unchanged.
March 2013: Congratulations to all - trial passes 3,700 patients.
January 2013: Welcome to Turkey and well done for recruiting your first patient: Professor Serefnur Ozturk of Selcuk University.
January 2013: Congratulations to everyone involved in the trial: we have reached our 3,500 participant target!
November 2012: Data Monitoring Committee recommend trial continues unchanged.
November 2012: Congratulations to all - ENOS passes 3,400 patients. Please keep recruiting, especially very early on after stroke onset.
September 2012: Congratulations to all - ENOS passes 3,300 patients.
June 2012: Data Monitoring Committee say carry on.
April 2012: CONGRATULATIONS TO ALL - ENOS reaches and passes 3,000 patients, a fantastic achievement.
December 2011: ENOS passes 2,700 patients. Well done to all recruiting sites.
November 2011: Congratulations to Dr Maia Beridze in Tbilisi for recruiting the first ENOS patient in Georgia. Dr Beridze is the National Coordinator.
August 2011: Fantastic news - ENOS passes 2,500 patients. Well done to all recruiting sites.
August 2011: Congratulations to Prof Hanne Christensen in Copenhagen for recruiting the first ENOS patient in Denmark. Dr Christensen is the National Coordinator.
June 2011: Data Monitoring Committee recommend trial continues unchanged.
April 2011: Congratulations to all recruiting centres - ENOS passes 2,300 participants.
January 2011: Trial Steering Committee meets.
October 2010: Congratulations to everyone - ENOS passes 1,000 participants in the continue-stop part of the trial.
September 2010: Congratulations to everyone - ENOS passes 2,000 participants.
July 2010: Congratulations to all - ENOS reaches 1,900 patients.
June 2010: Congratulations to Dr Valeria Caso in Perugia for recruiting the first ENOS patient in Italy. Dr Caso is the National Coordinator.
June 2010: Data Monitoring Committee recommend trial continues unchanged.
May 2010: Congratulations to all - ENOS reaches 1,800 patients.
February 2010: Congratulations to all - ENOS reaches 1,700 patients.
December 2009: Congratulations to all - ENOS reaches 1,600 patients.
November 2009: Following their latest review of the data, the Data Monitoring Committee (PDF file) recommend that the trial should continue.
November 2009: Congratulations to all - ENOS reaches 1,500 patients.
August 2009: Congratulations to all - ENOS reaches 1,400 patients.
August 2009: Congratulations to Dr Ronan Collins in Dublin for recruiting the first ENOS patient in Eire. Dr Collins is the National Coordinator.
June 2009: Congratulations to all - ENOS makes 1,300 patients.
May 2009: Following their latest review of the data, the Data Monitoring Committee (PDF file) recommend that the trial should continue.
April 2009: Congratulations to Professor Exuperio Tejedor in Madrid for recruiting the first ENOS patient in Spain. Professor Tejedor is the National Coordinator.
March 2009: Congratulations to Professor Szabolcs Szatmari in Targu Mures for recruiting the first ENOS patient in Romania. Professor Szatmari is the National Coordinator.
March 2009: Congratulations to Professor Anwar Etribi in Cairo for recruiting the first ENOS patient in Egypt. Professor Etribi is the National Coordinator. Start-up of the trial in Egypt means that ENOS is now operating in 5 continents!
March 2009: Congratulations to all - ENOS makes 1,200 patients. Thanks to all who have contributed to this great success.
January 2009: Apologies but the earlier comment that January was the highest recruiting month ever in ENOS was incorrect. However, 31 patients were enrolled into the trial which is still very credible.
December 2008: Following their latest review of the data, the Data Monitoring Committee (PDF file) recommend that the trial should continue.
December 2008: Excellent news - ENOS makes 1100 patients. Thanks to all the patients and investigators who have contributed to this important milestone.
October 2008: ENOS has its highest recruiting month ever at 34 patients. Thanks to all the investigators who have made it possible, and especially those who are managing to enrol more than one patient per month: AIIMS/New Delhi, India; Blackpool, UK; Derby, UK; Dunedin, New Zealand; Kirkcaldy, UK; .
August 2008: Fantastic news - ENOS makes 1000 patients. Thanks to all who have contributed to this massive endeavour: investigators, patients and staff. And now for the second 1000 - good luck!
August 2008: Congratulations to Prof Prasad and colleagues (AIIMS, Delhi) for enrolling the first ENOS patient in India. Prof Prasad is also the National Coordinator for India.
May 2008: Many thanks to all the investigators and potential investigators who attended the ENOS Stand and Investigator meeting at the European Stroke Conference in Nice.
April 2008: Congratulations to all the investigators - ENOS reaches 900 patients.
April 2008: Many thanks to all the potential investigators who attended the ENOS Investigator meeting at the V International Ischaemic Stroke Workshop in Madrid.
January 2008: The updated protocol and associated documents have been approved by MREC (National Ethics) and the MHRA (competent authority) in the UK. This brings the trial right up to date in approvals. The approvals documents are mounted on the Investigator website.
December 2007: Well done to United Lincolnshire Hospitals who recruited 10 patients between 1 November and end December and won GBP 500.
December 2007: Following their latest review of the data for 795 patients, the Data Monitoring Committee (PDF file) recommend that the trial should continue.
December 2007: Thanks to all the current and potential Investigators who attended the ENOS stand at 2nd UK Stroke Forum (UKSF) in Harrogate.
November 2007: Congratulations to all the investigators - ENOS reaches 800 patients. And special thanks to Yeovil District Hospital who found the 800th patient - they have a free registration to attend The European Stroke Conference in Nice in May 2008.
June 2007: Congratulations to all the investigators - ENOS reaches 700 patients.
May 2007: Thanks to all the Investigators who attended the ENOS meeting and/or stand at the European Stroke Conference in Glasgow.
March 2007: Congratulations to all investigators - ENOS reaches 600 patients. And thanks to Stepping Hill, Stockport in the UK for making it 600!
February 2007: We are very pleased to welcome Dr Graham Venables as the incoming independent Chairman of the Trial Steering Committee.
January 2007: The Stroke exemplar within the MRC NeuroGRID project, which comprises ENOS and IST-3, has been published in the International Journal of Stroke (February 2007, volume 2, issue 1)
January 2007: Annual Trial Steering Committee (TSC) held. We would like to thank Professor Daffyd Thomas, who has recently retired, for guiding us from the begining of the trial as the independent Chairman of the TSC. Daffyd has always been very supportive and we wish him well in retirement. Daffyd will remain as Chair until we appoint successor.
December 2006: Congratulations to all the investigators - ENOS reaches 550 patients.
December 2006: Following their latest review of the data for 520 patients, the Data Monitoring Committee (PDF file) recommend that the trial should continue.
December 2006: ENOS has its own stand at The UK Stroke Forum (in Harrogate)
November 2006: Main phase of trial commences!
October 2006: Trial protocol is published in International Journal of Stroke (November 2006, volume 1, issue 4)
August 2006: Congratulations to all the investigators - ENOS reaches 500 patients. And thanks to Singapore for making it 500!
June 2006: Congratulations to Dr Jayathissa and colleagues (Hutt Valley) for enrolling the first ENOS patient in New Zeland. Dr John Gommans (Hawkes Bay) is the National Coordinator.
May 2006: Media coverage of trial: UK Saga FM Radio
April 2006: UK Stroke Research Network (UKSRN) 'adopts' ENOS. Also see UK Clinical Research Network (UKCRN)
April 2006: Congratulations to Professor L Wong and colleagues for enrolling the first ENOS patient in Hong Kong
April 2006: Medical Research Council funds the main phase of ENOS which will commence in September 2006. Congratulations to all the Investigators for supporting the trial without which this funding would not have been made
Feb 2006: First Belgium site (Leige, Dr Desfontaines) joins trial
Dec 2005: Congratulations to Professor Y-Y Wang, Dr X Gong and colleagues for enrolling the first ENOS patient in China
Dec 2005: Please note new contact telephone and fax numbers
Nov 2005: New Zealand Stroke Trials Network (NZSTN) review and approve ENOS, and recommend it to their sites
Oct 2005: Congratulations to all the investigators - ENOS passes 400 patients
Oct 2005: Thanks to BUPA Foundation who have extended the trial's start-up funding for up to 5 months to August 2006
Summer 2005: Media coverage: Queen's Medical Centre
May 2005: Congratulations to Professor C Bladin and colleagues for enrolling the first 2 ENOS patients in Australia
Apr 2005: Congratulations to all the investigators - Now the largest ever randomised controlled trial to assess blood pressure management in acute stroke
Feb 2005: Australia joins ENOS
Jan 2005: Congratulations to Dr C Chen and colleagues in Singapore for being funded by A*STAR for the ENOS MRI sub-study
Dec 2004: Congratulations to all the investigators - ENOS passes 300 patients
Aug 2004: Medical Research Council (MRC) funds NeuroGRID. ENOS is an exemplar project within NeuroGRID
Feb 2004: Media coverage of trial: BBC News, Medical News Today, UK Saga FM Radio
Dec 2003: UK BUPA Foundation funds ENOS start-up phase for 400 patients
Oct 2003: Canadian Stroke Consortium (CSC) review and approve ENOS, and recommend it to their sites
Sep 2003: Australasian Stroke Trials Network (ASTN) review and approve ENOS, and recommend it to their sites
Jun 2003: Now bigger than all the existing randomised data for nitric oxide donors in acute stroke
Mar 2003: Now the largest trial of a nitric oxide donor in acute stroke

ENOS trial

Enter ENOS trial site

Documents

Main publication:
Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial (pdf) in The Lancet, 22 October 2014

Presentations/publications/listings

ENOS has been presented regularly at stroke conferences since 2001, including:

Recent attendances include:

October 2014: World Stroke Congress, Istanbul, Turkey
May 2014: European Stroke Conference, Nice, France
February 2014: ISC, San Diego, USA
December 2013 - UK Stroke Forum, Harrogate
October 2013: World Stroke Day, Wigan, UK
August 2013: Nordic Stroke Conference, Vilnius, Lithuania
May 2013: European Stroke Conference in London, UK
February 2013 - International Stroke Conference/American Stroke Association, Honolulu, USA
December 2012 - 7th UK Stroke Forum (stand H74), Glasgow, UK
October 2012 - 8th World Stroke Congress (stand #35), Brasilia, Brazil
May 2012 - 21st European Stroke Conference (stand 525), Lisbon, Portugal
February 2012 - International Stroke Conference/American Stroke Association, Los Angeles, USA
December 2011 - UK Stroke Forum, Glasgow, UK
May 2011 - European Stroke Conference, Hamburg, Germany
February 2011 - International Stroke Conference/American Stroke Association, Los Angeles, USA
December 2010 - UK Stroke Forum, Glasgow, UK
October 2010 - 7th World Stroke Congress, Seoul, South Korea
September 2010 - European Union Geriatric Medicine Society, Dublin, Eire
July 2010 - NIHR Stroke Research Network Annual Conference, Newcastle, UK
May 2010 - European Stroke Conference, Barcelona, Spain
February 2010 - International Stroke Conference/American Stroke Association, San Antonio, USA
January 2010 - West Midlands Stroke Research Network, Birmingham, UK
December 2009 - UK Stroke Forum, Glasgow, UK
July 2009 - UK Stroke Research Network Annual Conference, Newcastle, UK
May 2009 - European Stroke Conference, Stockholm, Sweden
May 2009 - Peninsula Stroke Research Network Annual Conference, Exeter, UK
February 2009 - International Stroke Conference/American Stroke Association, San Diego, USA
December 2008 - 3rd UK Stroke Forum (UKSF) in Harrogate, UK.
October 2008 - 56th Irish Gerontological Society Scientific meeting in Kilkenny, Eire.
October 2008 - Northern Ireland Multidisciplinary Association for Stroke Teams meeting.
October 2008 - Scottish Stroke Research Network meeting.
October 2008 - 12th Asian Oceanian Congress of Neurology (AOCN 2008)/16th Annual Conference of Indian Academy of Neurology (IAN) in New Delhi, India.

Trial protocol:

The ENOS Trial Investigators. Glyceryl trinitrate vs. control, and continuing vs. stopping temporarily prior antihypertensive therapy, in acute stroke: rationale and design of the Efficacy of Nitric Oxide in Stroke (ENOS) trial (ISRCTN99414122). International J Stroke 2006;1:245-249

Other selected presentations, publications and listings include:

Is lowering blood pressure hazardous in patients with significant ipsilateral carotid stenosis and acute ischaemic stroke? Interim assessment in the 'Efficacy of Nitric Oxide in Stroke' Trial. Blood Pressure Monitoring 2009;14(1):20-25
The NeuroGrid stroke exemplar clinical trial protocol. International Journal of Stroke 2007;2:63-69
Effect of nitric oxide donors on blood pressure and pulse pressure in acute and subacute stroke. J Stroke Cerebrovascular Diseases 2006;15:245-249
Continuing prior antihypertensive medication in acute stroke lowers blood pressure: Data from the continue vs stop arm of the 'Efficacy of Nitric Oxide in Stroke' (ENOS) trial. World Congress of Neurology, Sydney, November 2005
ENOS Efficacy of Nitric Oxide in Stroke Trial. Stroke Center Stroke Trials Registry 2002
Management of blood pressure in acute stroke. Canadian J Neurological Sciences 2002;29;404

The Virtual Medical Centre has produced some videos with Lesley Cala, scan adjudicator on ENOS, which involve ENOS:
'Improving Stroke Outcomes' (link), 10/09/2015
For the following video you will need to sign up here: this is free but only registered health professionals (who input the required registration numbers) will be able to view this video.
ENOS trial (link), 10/09/2015.

Demo/practice website and database

Enter demo/practice ENOS trial site

Please note that data entered into the demo/practice website and database is not entered into the main/full trial database and does not contribute to trial data. However, this website and database replicates and demonstrates the functions of the main trial website and database.

Study personnel

Trial Steering Committee:

Independent Chairman - Graham Venables (Sheffield); Independent experts - Pierre Amarenco (Paris, France), Keith Muir (Glasgow); Members - Philip Bath (Nottingham), Kennedy Lees (Glasgow), Stuart Pocock (London), Joanna Wardlaw (Edinburgh), David Whynes (Nottingham), Eivind Berge (Oslo, Norway); EME/MRC representative - Jane Sinclair (Southampton); University of Nottingham/sponsor representative - Angela Shone

International Advisory Committee:

Chair - Philip Bath, Australia - TBA, Canada - Stephen Phillips, China - Yong-Jun Wang, Egypt - Anwar El Etribi, Republic of Ireland - Ronan Collins, Georgia - Maia Beridze, Greece - George Ntaios, Hong Kong - Lawrence Wong, India - Kameshwar Prasad, Italy - Valeria Caso, Malaysia - Abdul Raman Ghani, New Zealand - John Gommans, Norway - Eivind Berge, Poland - Anna Czlonkowska, Romania - Szabolcs Szatmari, Saudi Arabia - Mohammed Al Jumah, Singapore - Hui Meng Chang, Spain - Exuperio de Tejedor, Sri Lanka - Asita de Silva, Sweden - Ann Charlotte Laske, UK - Kennedy Lees

Trial Management Committee (Nottingham):

Chief Investigator - Philip Bath, Trial Manager - Sally Utton, Assistant Trial Manager - Hayley Foster, Medic - Kailash Krishnan, UK Coordinators - Tanya Payne & Margaret Adrian, International Coordinators - Alice Durham & Sarah Grant, Outcome Coordinator - Joanne Keeling, Statisticians - Lisa Woodhouse & Polly Scutt, Data/Imaging Coordinator - Tanya Jones, Programming - Lee Haywood, Liz Walker, Finance - Wim Clarke, Secretary - Yvonne Smallwood

Independent Data Monitoring Committee:

Chairman - Peter Sandercock (UK); Members - Kjell Asplund (Sweden), Colin Baigent (UK); Statistician - Lucy Bradshaw (UK)

Independent Events Adjudicator:

Daniel Bereczki (Hungary), Nikola Sprigg (UK)

Scan Adjudicators:

Joanna Wardlaw (Chair), Alessandro Adami (Italy), Jennifer Becker (USA), Lesley Cala (Australia), Ana Casado (UK), Rob Dineen (UK), Panayiotis Koumellis (UK)

Programming/database management:

Lee Haywood, Liz Walker (UK)

Contact details

ENOS Trial Office

Stroke, Division of Clinical Neuroscience

University of Nottingham

Clinical Sciences Building

City Hospital campus

Hucknall Road

Nottingham NG5 1PB

Telephone: +44 (0)115 823 1770

Fax: +44 (0)115 823 1771

E-mail:enos@nottingham.ac.uk

Written by Philip Bath, last updated by Dawn Hazle 11th September 2015