Efficacy of Nitric Oxide in Stroke-2
| ISRCTN | ISRCTN17654248 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17654248 |
| EudraCT/CTIS number | 2020-001304-42 |
| IRAS number | 281728 |
| Secondary identifying numbers | CPMS 45528, IRAS 281728 |
- Submission date
- 23/03/2021
- Registration date
- 31/03/2021
- Last edited
- 23/04/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English Summary
Background and study aims
When someone has a stroke there are a few hours after the symptoms begin where the brain cells are at risk of dying but may still be saved. It is possible to give treatments for stroke to help save these ‘at-risk’ brain cells during the few hours and therefore prevent further injury. New treatments are being developed to treat stroke more effectively, but it can be very hard to test whether they work in the first few hours because often patients take longer than this to get to hospital.
High blood pressure is common in the first hours and days following a stroke and increases the risk of patients 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 doctors routinely treat high blood pressure long term after a stroke, they do not do so immediately after the stroke.
The aim of this study is to test a treatment that lowers blood pressure when given immediately on arrival at hospital and soon after patients have had a stroke.
The treatment is called glyceryl trinitrate (commonly known as GTN) and it is a tried and tested drug in other medical conditions such as angina. It acts quickly to relax blood vessels and lowers blood pressure which is very important after stroke. GTN has also been tested in more than 4000 patients with recent stroke and was safe and lowered blood pressure. Of these, a few hundred patients received treatment between 3 and 5 hours after stroke and appeared to benefit from a better outcome. More patients in this narrow time window now need to be tested, rather than earlier than 3 hours or after 5 hours because lowering blood pressure with GTN appears not to be beneficial then.
The results of the trial will help doctors decide whether blood pressure lowering treatments like GTN should be given to patients soon after they have a stroke to give them a better chance of recovery.
Who can participate?
Patients aged 18 years or above arriving at hospital with symptoms that suggest they have had a stroke (either a clot or a bleed)
What does the study involve?
Once a potential participant has been confirmed to have had a stroke, the study will be explained to them by the research staff. If they agree to continue to take part, they will be asked to sign a consent form. If the participant has some problems signing then either a relative can sign for them or the research team can record that they have said that they have would like to continue to take part. The participant will have had all the normal medical tests and treatments for stroke. The hospital staff will then put a patch on the participants back followed by a further patch the day after their stroke. If the participant leaves hospital before the second patch, they won’t need any more patches.
The patches will have either contain blood pressure lowering medicine or won’t have any medicine in them. The decision about what patches the participants get will be decided by chance (rather like tossing a coin) and neither the participant nor the doctor or nurse are able to choose. This is called randomisation and is done by a special computer programme. This is important as it makes sure equal numbers of patients receive each treatment. This means it is a fair test between treatments. The patch is covered in gauze to try to make sure that the participant or their relatives and friends and the medical staff do not know what treatment they have had. This makes the design of the trial better. If they continue to take part in the study, they will still receive all the care that they would normally receive after a stroke.
At 3 and 12 months after the stroke, a researcher will telephone the participant. They will ask a number of questions to see how well they have recovered from the stroke.
What are the possible benefits and risks of participating?
Participation may reduce the symptoms of the stroke or improve long-term recovery. However, this cannot be promised. The information obtained from the study may benefit other people who have a stroke in the future. All drugs have the possibility of side effects. The side effects from the blood pressure lowering patch are generally mild. The research team will check if the participant has experienced any side effects from the patch. If so the patch can be removed.
Where is the study run from?
University of Nottingham (UK)
When is the study starting and how long is it expected to run for?
April 2020 to September 2024
Who is funding the study?
Nottingham Hospital's Charity Research Fund (UK)
Who is the main contact?
Diane Havard
diane.havard@nottingham.ac.uk, enos-2@nottingham.ac.uk
Contact information
Public
Stroke Trials Unit
Mental Health & Clinical Neurosciences
University of Nottingham
D Floor, South Block, Room 2151
Queens Medical Centre
Nottingham
NG7 2UH
United Kingdom
 ORCID ID |
0000-0002-3257-1137 |
|---|---|
| Phone | +44 (0)1158231775 |
| diane.havard@nottingham.ac.uk |
Scientific
Stroke Trials Unit
Mental Health & Clinical Neurosciences
University of Nottingham
D Floor, South Block
Queens Medical Centre
Nottingham
NG7 2UH
United Kingdom
| ORCID ID |
0000-0003-2734-5132 |
|---|---|
| Phone | +44 (0)1158231765 |
| philip.bath@nottingham.ac.uk |
Study information
| Study design | Prospective randomized single-blinded masked-endpoint phase IIb trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN17654248_PIS_ V1.2_01Jul2020.docx |
| Scientific title | Efficacy of Nitric Oxide in Stroke-2 |
| Study acronym | ENOS-2 |
| Study hypothesis | To assess the feasibility of recruitment and safety of transdermal glyceryl trinitrate (GTN) versus sham applied between 3 and 5 hours of stroke to inform a definitive trial. |
| Ethics approval(s) | Approved 30/06/2020, North West - Greater Manchester South Research Ethics Committee (3rd Floor, Barlow House, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 (0)207 104 8010; gmsouth.rec@hra.nhs.uk), REC ref: 20/NW/0246 |
| Condition | Stroke |
| Intervention | Current intervention as of 19/05/2022: Patients will be randomized (1:1) to receive either glyceryl trinitrate patches or sham patches. Randomization will be performed by the Nottingham Stroke Trials Unit (STU) and involve computerised stratification by stroke type (IS or not known; ICH) and minimisation on age, severity, time, systolic blood pressure and candidate for or received reperfusion therapy. Patients, relatives, researchers and outcome assessors will be masked to treatment allocation Active: Transdermal glyceryl trinitrate (GTN) 5 mg placed on back or shoulders and applied for 2 days. Comparator: Transdermal Duoderm hydrocolloid dressing placed on back or shoulders and applied for 2 days. Following 2 days of treatment both arms will have the same follow up - follow-ups will be carried out on Day 2, the day of death or discharge from hospital, and Day 90. _____ Previous intervention: Patients will be randomized (1:1) to receive either glyceryl trinitrate patches or sham patches. Randomization will be performed by the Nottingham Stroke Trials Unit (STU) and involve computerised stratification by stroke type (IS or not known; ICH) and minimisation on age, severity, time, systolic blood pressure and candidate for or received reperfusion therapy. Patients, relatives, researchers and outcome assessors will be masked to treatment allocation Active: Transdermal glyceryl trinitrate (GTN) 5 mg placed on back or shoulders and applied for 2 days. Comparator: Transdermal Duoderm hydrocolloid dressing placed on back or shoulders and applied for 2 days. Following 2 days of treatment both arms will have the same follow up - follow-ups will be carried out on Day 2, the day of death or discharge from hospital, day 90 and day 365. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Glyceryl trinitrate |
| Primary outcome measure | Current primary outcome measures as of 26/05/2022: 1. Feasibility of recruitment assessed using recruitment data recorded throughout the 31 months of recruitment 2. Safety assessed using safety monitoring throughout the study _____ Previous primary outcome measure: The feasibility of recruiting 120 (100 ischaemic stroke/20 intra-cerebral haemorrhage) eligible stroke patients who consent to participate in the study within 12 months of the start date |
| Secondary outcome measures | Current secondary outcome measures as of 26/05/2022: 1. Blood pressure measured using standard sphygmomanometer at baseline, Day 0 post treatment, Day 1 during treatment 2. Disability measured using the National Institutes of Health Stroke Scale (NIHSS) at baseline and Day 2 3. Feeding and dysphagia measured using the Dysphagia Severity Rating Scale (DSRS) at Day 2 4. Hospital utilisation (thrombectomy, hemicraniectomy surgery, hyperacute stroke unit, rehabilitation, physiotherapy, occupational therapy, speech and language therapy, ITU use) measured by review of medical notes at death/discharge 5. Functional ability measured using the modified Rankin scale (mRS) and Barthel index (BI) at Day 90 6. Cognition measured using the mini mental state examination (MMSE) at Day 90 7. Mood measured using the Zung Depression Scale (ZDS) at Day 90 8. Quality of life measured using EuroQoL (EQ5D) at Day 90 _____ Previous secondary outcome measures: 1. Blood pressure measured using standard sphygmomanometer at baseline, Day 0 post treatment, Day 1 during treatment 2. Disability measured using the National Institutes of Health Stroke Scale (NIHSS) at baseline and Day 2 3. Feeding and dysphagia measured using the Dysphagia Severity Rating Scale (DSRS) at Day 2 4. Hospital utilisation (thrombectomy, hemicraniectomy surgery, hyperacute stroke unit, rehabilitation, physiotherapy, occupational therapy, speech and language therapy, ITU use) measured by review of medical notes at death/discharge 5. Functional ability measured using the modified Rankin scale (mRS) and Barthel index (BI) at Day 90 and Day 365 6. Cognition measured using the mini mental state examination (MMSE) at Day 90 and Day 365 7. Mood measured using the Zung Depression Scale (ZDS) at Day 90 and Day 365 8. Quality of life measured using EurolQuol (EQ5D) at Day 90 and Day 365 |
| Overall study start date | 01/04/2020 |
| Overall study end date | 30/09/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 120 |
| Total final enrolment | 39 |
| Participant inclusion criteria | Current inclusion criteria as of 19/05/2022: 1. Adults (aged ≥18 years) 2. Presentation compatible with hyperacute stroke syndrome 3. One or more of the following symptoms present at time of enrolment: Dysphasia, neglect (NIHSS 1-2), hemianopia (NIHSS 1-3), or limb weakness (NIHSS on affected arm and/or leg 1-4) 4. Treatment can be commenced between 3 and 5 h from onset of symptoms (for patients with wake-up stroke, treatment no more than 5 h after patient awakens) 5. Systolic BP ≥120 mmHg 6. If a CT/MR scan has already been performed, then it shows acute intracerebral haemorrhage or ischaemic stroke, or is normal. (If a CT scan has not been performed then it should be performed as soon as possible after treatment.) 7. For participants who lack capacity to consent for themselves and have no relative/friend available: Waiver of consent for treatment to ensure GTN given in 3- to 5-h time-window (and thrombolysis not delayed if ischaemic stroke) _____ Previous inclusion criteria: 1. 120 adults (≥18 years old) with presentation compatible with stroke) 2. Treatment 3-5 hours post ictus (or from when last seen free of stroke symptoms) 3. Limb weakness at time of enrolment (NIHSS on affected are and/or leg 1-4) 4. Systolic blood pressure (≥120 mmHg) 5. If a CT/MR scan has already been performed, then it shows acute intracerebral haemorrhage or ischaemic stroke, or is normal 6. Waiver of consent for treatment to ensure GTN given in 3-5 hour time-window (and thrombolysis not delayed if ischaemic stroke) |
| Participant exclusion criteria | Current exclusion criteria as of 19/05/2022 (following amendment approved 18/05/2022): 1. mRS ≥4 2. Hypotension or shock (systolic <120 mmHg) 3. BP Glucose (BM stix or equivalent) <3 mmol/l 4. Glasgow coma scale ≤8 5. Witnessed seizure at presentation 6. Known life expectancy <6 months 7. Patient presenting with sensory symptoms only 8. Known stroke mimic, aneurysmal subarachnoid haemorrhage, or haemorrhage due to venous thrombosis 9. Known allergy to glyceryl trinitrate (Transiderm-Nitro) patch 10. Known sensitivity to Duoderm hydrocolloid dressing 11. Planned for palliative care only 12. Recent use of phosphodiesterase type 5 (PDE5) inhibitors, e.g., sildenafil (Viagra®) 13. If a CT/MR scan has already been performed, then it shows a non-stroke lesion that explains the acute presentation 14. Known previous enrolment in ENOS-2 _____ Previous exclusion criteria as of 03/09/2021 (following amendment approved 25/08/2021): 1. mRS ≥4 2. Glucose (BM stix or equivalent) <3 mmol/l 3. Glasgow coma scale ≤8 4. Witnessed seizure at presentation 5. Known life expectancy <6 months 6. Known stroke mimic, aneurysmal subarachnoid haemorrhage, or haemorrhage due to venous thrombosis 7. Systolic blood pressure <120 mmHg 8. Known allergy to glyceryl trinitrate (Transiderm-Nitro) patch 9. Known sensitivity to Duoderm hydrocolloid dressing 10. Planned for palliative care only 11. Known previous enrolment in ENOS-2 _____ Previous exclusion criteria: 1. Patient from a nursing home 2. Glucose (BM stix or equivalent) <3 mmol/l 3. Glasgow coma scale ≤8 4. Witnessed seizure at presentation 5. Known life expectancy <6 months 6. Known stroke mimic, aneurysmal subarachnoid haemorrhage, or haemorrhage due to venous thrombosis 7. Systolic blood pressure <120 mmHg 8. Known allergy to glyceryl trinitrate (Transiderm-Nitro) patch 9. Known sensitivity to Duoderm hydrocolloid dressing 10. Planned for palliative care only 11. Known previous enrolment in ENOS-2 |
| Recruitment start date | 29/07/2021 |
| Recruitment end date | 29/06/2024 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
Sponsor information
University/education
Research and Innovation
E-Floor Office, Yang Fujia Building
Jubilee Campus
Wollaton Road
Nottingham
NG8 1BB
England
United Kingdom
| Phone | +44 (0)1158231765 |
|---|---|
| bb-sponsor@nottingham.ac.uk | |
| Website | http://www.nottingham.ac.uk |
"ROR" |
https://ror.org/01ee9ar58 |
Funders
Funder type
Charity
No information available
Results and Publications
| Intention to publish date | 31/05/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Publication in a peer-reviewed high impact journal |
| IPD sharing plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version V1.2 | 01/07/2020 | 31/03/2021 | No | Yes |
| Participant information sheet | version 1.2 | 14/05/2021 | 27/10/2021 | No | Yes |
| Participant information sheet | version 1.3 | 12/04/2022 | 19/05/2022 | No | Yes |
| Protocol file | version 3.0 | 14/09/2022 | 03/02/2023 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol file | version 4.0 | 01/03/2024 | 14/04/2025 | No | No |
| Statistical Analysis Plan | 30/06/2024 | 14/04/2025 | No | No | |
| Basic results | 15/04/2025 | 23/04/2025 | No | No |
Additional files
- ISRCTN17654248_PIS_ V1.2_01Jul2020.docx
- Uploaded 31/03/2021
- ISRCTN17654248_PIS_v1.2_14May21.pdf
- ISRCTN17654248_PIS_V1.3_12Apr2022.pdf
- 39677 ENOS-2 PROTOCOL Final V3.0 14Sep2022.pdf
- ISRCTN17654248 ENOS-2 protocol 01Mar2024 v4.0 final.pdf
- ISRCTN17654248 ENOS-2 SAP 30Jun2024.pdf
- ISRCTN17654248_BasicResults_15Apr25.pdf
Editorial Notes
23/04/2025: Basic results and total final enrolment added.
14/04/2025: The following changes were made to the trial record:
1. The statistical analysis plan was uploaded as an additional file.
2. Uploaded protocol v4.0 (not peer-reviewed) as an additional file.
18/06/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/05/2024 to 29/06/2024.
2. The overall end date was changed from 30/06/2024 to 30/09/2024.
3. The plain English summary was updated to reflect these changes.
10/05/2024: The overall study end date was changed from 31/05/2024 to 30/06/2024.
20/02/2024: The recruitment end date was changed from 29/02/2024 to 31/05/2024.
06/02/2023: Internal review.
03/02/2023: Uploaded protocol (not peer-reviewed) as an additional file.
26/05/2022: The following changes have been made:
1. The primary outcome measures have been changed.
2. The secondary outcome measures have been changed.
3. The participant exclusion criteria have been updated to include the dates of amendment approval. 19/05/2022: The following changes have been made:
1. The overall trial end date has been changed from 28/07/2023 to 31/05/2024.
2. The participant inclusion criteria have been changed.
3. The participant exclusion criteria have been changed.
4. The recruitment start date has been changed from 28/07/2021 to 29/07/2021.
5. The recruitment end date has been changed from 28/07/2022 to 29/02/2024.
6. The intention to publish date has been changed from 31/07/2023 to 31/05/2025.
7. The scientific contact's details have been updated.
8. The sponsor contact details have been updated.
9. Participant information sheet version 1.3 has been added.
10. The plain English summary has been updated to reflect the above changes.
27/10/2021: The following changes have been made:
1. The participant information sheet has been uploaded as an additional file.
2. The overall trial end date has been changed from 30/04/2023 to 28/07/2023 and the plain English summary has been updated to reflect this change.
3. The study contact has been updated.
29/09/2021: The trial website has been added.
03/09/2021: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/05/2021 to 28/07/2021.
2. The recruitment end date was changed from 30/04/2022 to 28/07/2022.
3. The exclusion criteria were updated.
23/03/2021: Trial's existence confirmed by North West - Greater Manchester South Research Ethics Committee.
