E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Assess the balance of risk and benefit of lowering blood pressure with GTN immediately after ischaemic and haemorrhagic stroke. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: Assess whether pre-stroke antihypertensive therapy should be continued or stopped temporarily after stroke. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Genetic sub-study: An important aim of the genetic analyses is to determine whether polymorphic differences in candidate genes explain blood pressure and outcome responses to GTN (pharmacogenetic analysis). The exact genetic analyses to be performed are undefined at present and will depend on relevant scientific information available at the time of laboratory analysis and prior to sample destruction. Likely analyses will include genes related to the synthesis and metabolism of nitric oxide (e.g. endothelial nitric oxide synthase) and the mechanism of action of antihypertensive agents (e.g. polymorphisms in receptors) |
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E.3 | Principal inclusion criteria |
a) Adult (age > 18 years). b) Clinical stroke syndrome with limb weakness lasting at least 1 hour (i.e. not likely to be a transient ischaemic attack). c) Residual limb weakness at the time of enrolment (SSS Arm <6 and/or Leg <6, appendix C). d) Onset < 48 hours. If the time of onset is unknown, apply the time when the patient was last known to be well. [This timeframe covers the period of maximum uncertainty over altering blood pressure and should permit the vast majority of otherwise eligible patients to be recruited] e) Conscious (Glasgow Coma Scale > 8). f) Systolic blood pressure in range 140 mmHg to 220 mmHg inclusive on the basis of at least one of the three baseline pre-randomisation measures. g) Independent prior to stroke (pre-morbid modified Rankin Scale < 2). h) Meaningful consent, or assent from a relative or carer if the patient is unable to give meaningful consent (e.g. in cases of dysphasia, confusion, or reduced conscious level).
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E.4 | Principal exclusion criteria |
a) Definite need for nitrate therapy: e.g. concurrent myocardial infarction, unstable angina, left ventricular failure. Patients admitted on nitrates for the management of stable angina may stop these for the 7 day trial treatment period. b) Contraindication to nitrate therapy: e.g. hypersensitivity to nitrates, dehydration, hypovolaemia, hypertrophic obstructive cardiomyopathy, aortic stenosis, cardiac tamponade, constrictive pericarditis, mitral stenosis, marked anaemia, closed-angle glaucoma, sildenafil (Viagra) or related drug, within 24 hours. c) Definite need for pre-stroke antihypertensive, anti-anginal or anti-heart failure medication: e.g. concurrent angina, heart failure. d) Definite need for new antihypertensive, anti-anginal or anti-heart failure medication during acute stroke: e.g. concurrent angina, heart failure, hypertensive encephalopathy, aortic dissection. e) Patients expected, on the basis of existing investigations, to require surgical intervention (e.g. clot evacuation, carotid endarterectomy) during the treatment or follow-up period. f) Known intracerebral pathology other than stroke, e.g. subarachnoid haemorrhage, brain tumour, cerebral abscess. g) Other serious condition which is likely to prevent outcome assessment at 90 days, e.g. advanced cancer. h) Previous enrolment in ENOS. i) Current involvement in another trial of an experimental drug. [Patients may be randomised into observational studies or non-drug trials.] j) Not available for follow-up, e.g. no fixed address, overseas visitor. k) Females of childbearing potential where pregnancy cannot be excluded by a negative pregnancy test, pregnancy, or breastfeeding. l) Need for new antihypertensive therapy to lower systolic blood pressure to achieve the enrolment range of 140-220mmHg m) New (not prescribed pre-stroke) antihypertensive medication commenced after stroke onset
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E.5 End points |
E.5.1 | Primary end point(s) |
Combined death or dependency (modified Rankin Score >2) evaluation of this endpoint: 90 days after stroke onset
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Page 21 of 61 Events at or within 7 days (enter on ‘day 7’ form): a) Recurrent stroke. b) Scandinavian Stroke Scale (SSS) score. c) Symptomatic deep vein thrombosis. d) Symptomatic pulmonary embolism. e) Adverse events - headache, symptomatic hypotension.
Haemodynamic (enter on ‘day 7’ form): a) Blood pressure daily between 1 and 7 days (see section 2.13).
Hospital events (enter on ‘hospital events’ form): a) Length of stay in hospital. ENOS PROTOCOL, version 1.5, 10th July 2008 Philip Bath, telephone: +44 115 823 1768; fax: +44 115 823 1771; e-mail philip.bath@nottingham.ac.uk b) Discharge disposition (death, institution, or home). c) Time at home
Outcome at 90 days (to be collected centrally): a) Barthel Index (< 60/100, including death). b) Barthel Index (< 60/100, excluding death), i.e. disability. c) Barthel Index > 95/100 at 90 days, i.e. an excellent outcome 5,142. d) Quality of life – EuroQol.143 e) Cognition - , TICS-M144 and verbal fluency145. (see appendix G) f) Mood – Zung Depression rating Scale 146,147 g) Disposition. h) Re-hospitalisation following discharge
Safety measures at 7 days (enter on ‘day 7’ form): a) Death. b) Neurological deterioration. (negative change in SSS) c) Symptomatic intracranial haemorrhage. d) Major extracranial haemorrhage. e) Symptomatic hypotension. f) Symptomatic hypertension.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Patch or no patch under gauze dressing |
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E.8.2.4 | Number of treatment arms in the trial | 6 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 130 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
China |
Egypt |
Georgia |
Greece |
Hong Kong |
India |
Ireland |
Italy |
Malaysia |
New Zealand |
Norway |
Philippines |
Poland |
Romania |
Serbia |
Spain |
Sri Lanka |
Sweden |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |