E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
All patients found eligible for thrombolysis may enter the thrombolysis-arm (NOR-SASS I), all patients
with contraindications to thrombolysis within the 4 ½ hour time window may enter the no-thrombolysis-arm
(NOR-SASS II). |
|
E.1.1.1 | Medical condition in easily understood language |
Patient aged 18 or older with stroke, where treatment can be started within 4 1/2 hours of stroke onset. |
|
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061256 |
E.1.2 | Term | Ischaemic stroke |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
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 |
The primary analysis in NOR-SASS is to test whether Contrast enhanced sonothrombolysis (CEST) is superior to no CEST. |
|
E.2.2 | Secondary objectives of the trial |
The specific aims of the NOR-SASS are to
" Assess the effect on clinical short-term and long-term outcome of CEST
" Assess safety of the chosen algorithm
" Assess the effect on 2 hour and 24 hour recanalisation of combined CEST and intravenous thrombolysis versus intravenous thrombolysis alone.
" Assess the effect on 2 hour and 24 hour recanalisation of CEST versus no specific treatment
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria
Patients 18 years or older with acute ischaemic stroke
Treatment must be delivered within 4½ hours of symptom onset
Patients who fulfil NOR-TEST criteria for iv thrombolysis are eligible for the CEST arm
Patients who have a contraindication for thrombolysis are eligible for the CES arm
Informed written consent signed by the patient, verbal consent from the patient as witnessed by a non-participating health care person, or consent by the signature of the patient's family must be provided before treatment. Patients for whom no informed consent can be obtained will not be included in the study.
|
|
E.4 | Principal exclusion criteria |
Exclusion criteria
Patients with premorbid modified Rankin Scale (mRS) score ≥3;
· Patients for whom a complete NIH Stroke Score cannot be obtained;
· Hemiplegic migraine with no arterial occlusion on baseline CT;
· Seizure at stroke onset and no visible occlusion on baseline CT;
· Intracranial haemorrhage on baseline CT;
· Clinical presentation suggesting subarachnoid haemorrhage even if baseline CT is normal;
· Large areas of hypodense ischaemic changes on baseline CT;
· Patients with primary endovascular treatment;
· Female, pregnant or breast feeding; pericarditis; sepsis; any other serious medical illness likely to
interact with treatment; confounding pre-existent neurological or psychiatric disease; unlikely to
complete follow-up; any investigational drug <14 days;
Specific sonothrombolysis exclusion criteria
· known hypersensitivity/allergy to SonoVue;
· recent or unstable coronary ischemia or resting angina <7 days;
· acute cardiac insufficiency, cardiac insufficiency class III/IV; serious cardiac arrhythmias;
· any right-left-shunt; severe pulmonary hypertension (PAP >90 mmHg); uncontrolled hypertension;
· moderate to severe COPD (baseline O2 saturation <80%);
· acute respiratory distress syndrome (ARDS);
· no temporal “bone window” for ultrasound examination. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Periodic safety review is performed after each 40 enrolled patients.
(20 per group)
Functional handicap (modified Rankin Scale score) at 90 days |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
After each 40 enrolled patients.
On day 90. |
|
E.5.2 | Secondary end point(s) |
" Haemorrhagic transformation (haemorrhagic infarct / haematoma)
" Symptomatic cerebral haemorrhage
" Major neurological improvement at 24-36 hours
" Recanalisation at 2 hours and
" Recanalisation at 24-36 hours
Safety monitoring is performed by an independent Data safety and monitoring committee (DSMC).
Periodic safety review is performed after each 40 enrolled patients (20 per group). Formal interim analysis
is performed once a year. If the DSMC finds unacceptably increased symptomatic intracerebral
haemorrhage (SICH) with [CEST+TNK 0,4 mg/kg], i.e. a 2% excess of SICH as compared with
[CEST+tPA], the tier 0,4 mg/kg will be stopped and the study continued with TNK 0,25 mg/kg.
If [CEST+any thrombolysis] shows a 2% excess of SICH as compared with [any thrombolysis], the study
will be stopped. The same stopping rule will be applied to [CES] vs. [sham CES] in patients not eligible for
thrombolysis. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 2 hours
At 24-36 hours
|
|
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 13 |
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 | No |
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
|
|
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 | 4 |
E.8.9.1 | In the Member State concerned days | 0 |