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 | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042244 |
E.1.2 | Term | Stroke |
E.1.2 | System Organ Class | 100000004852 |
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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 |
To assess the effect of transdermal GTN, started within 3 hours of symptom onset in the prehospital setting, on functional outcome at 90 days in patients with acute ischaemic stroke or intracerebral haemorrhage. |
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E.2.2 | Secondary objectives of the trial |
To assess whether the effects of transdermal GTN, started within 3 hours of symptom onset in the prehospital setting, on functional outcome at 90 days are consistent across specific subgroups of patients, i.e., those with 1. ischaemic stroke; 2. ischaemic stroke treated with endovascular techniques; or 3. intracerebral haemorrhage.
To assess the effect of GTN on collaterals, size of the ischemic core and salvageable brain tissue on admission to the hospital.
To collect and analyse data regarding the deferred consent procedure and its association with patient recall and satisfaction at three months from randomisation.
To study the efficiency of national IAT implementation, given the availability of IAT hospitals and capacity, and travel times of ambulance services.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 18 years or older;
2. Probable diagnosis of acute stroke, as made by the paramedic in the prehospital setting;
3. Score of 2 or 3 on the Face Arm Speech Test (FAST);
4. Systolic blood pressure ≥ 140 mm Hg;
5. Possibility to start the trial treatment within 3 hours of symptom onset;
6. Intention to transport the patient to one of the participating hospitals;
7. Written informed consent (deferred).
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E.4 | Principal exclusion criteria |
1. Considerable pre-stroke dependency in activities of daily living, defined as staying in a chronic nursing home or rehabilitation centre;
2. Known glucose < 2.5 mmol/L;
3. Witnessed seizure at presentation;
4. Known life expectancy ≤ 1 year;
5. Known pregnancy or lactation;
6. Clinical indication for treatment with GTN;
7. Clinical indication for reduction of blood pressure;
8. Known hypersensitivity to GTN, nitrates in general, or the adhesives used in the patch
9. Glasgow Coma Scale < 8;
10. Known with any of the following heart disorders: myocardial insufficiency due to obstruction; aortic or mitral valve stenosis; constrictive pericarditis; hypertrophic obstructive cardiomyopathy; cardiac tamponade;
11. Known marked anaemia, defined as haemoglobin < 5 mmol/L;
12. Known closed angle glaucoma;
13. Known concomitant use of phosphodiesterase type-5 inhibitors, (e.g. sildenafil, tadalafil, vardenafil) or the soluble guanylate cyclase stimulator riociguat.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is the score on the modified Rankin Scale (mRS)54 at 90 days (± 14 days). The mRS is the preferred disability parameter for clinical trials in stroke. The mRS is an ordinal hierarchical scale incorporating six categories from 0 up to and including 5, and describes the range of disability encountered post stroke. ‘Death’ is assigned a score of 6. |
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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) |
On admission to the hospital:
Vital signs: first measured systolic and diastolic blood pressure, pulse, and body temperature;
Collateral circulation, as assessed with CTA (only in patients in whom CT angiography is performed as part of routine clinical care);
Lesion size: volume of the perfusion deficit (only in patients in whom CT perfusion is performed as part of routine clinical care) or ICH on the initial CT;
At 24 hours (± 4 hours):
Treatment with intravenous thrombolysis;
Intra-arterial treatment;
Vital signs: systolic and diastolic blood pressure, pulse, and body temperature;
Neurological deficit, as assessed with the NIHSS;
At 7 days (± 1 day) or at discharge, if earlier:
SAEs in the first 7 days or until discharge, if earlier;
At 90 days (± 14 days):
Death;
Dichotomized mRS of 0-1 vs. 2-6;
Dichotomized mRS of 0-2 vs. 3-6;
Dichotomized mRS of 0-3 vs. 4-6;
Disability assessed with the score on the Barthel Index56 (BI);
Quality of life assessed with the EuroQol 5D-5L (EQ-5D-5L);
Home time: the number of nights among the first 90 since stroke onset that are spent in the patient’s own home or a relative’s home. Resource use will be censored at 90 days. Where final follow-up occurs earlier, the last known placement will be extrapolated to 90 days;
Patient location over first 90 days (± 14 days): hospital; rehabilitation service; chronic nursing facility; home.
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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 | Yes |
E.8.1.3 | Single blind | No |
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 | No |
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 |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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Reasons for terminating may include
The incidence and severity of AEs in this/other studies indicates potential health hazard to subjects
Subject enrolment unsatisfactory
Data recording inaccurate/incomplete unacceptable extent
Investigator(s) do not adhere to the protocol or applicable regulatory guidelines in conducting this study
Submission of knowingly false information from study site to Sponsor or regulatory authorities
Results of an interim analysis supporting terminating study |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |