Stereotactic Cisternal Lavage in Patients with Aneurysmal Subarachnoid Hemorrhage with Urokinase and Nimodipine for the Prevention of Secondary Brain Injury. A Randomized Controlled Trial

INTERVENTION: Pharmaceutical Form: Solution for infusion INN or Proposed INN: NIMODIPINE CAS Number: 66085‐59‐4 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10 mg/50 ml‐ Pharmaceutical Form: Powder for solution for injection/infusion INN or Proposed INN: Urokinase CAS Number: 9039‐53‐6 Other descriptive name: UROKINASE Concentration unit: IU international unit(s) Concentration type: equal Concentration number: 50000‐ Pharmaceutical Form: Solution for infusion INN or Proposed INN: Calciumchlorid‐Dihydrat CAS Number: 8026‐10‐6 Other descriptive name: RINGER'S SOLUTION Concentration unit: g/l gram(s)/litre Concentration type: equal Concentration number: 0,33‐ INN or Proposed INN: Kaliumchlorid CAS Number: 8026‐10‐6 Other descriptive name: RINGER'S SOLUTION Concentration unit: g/l gram(s)/litre Concentration type: equal Concentration number: 0,3‐ INN or Proposed INN: Natriumchlorid CAS Number: 8026‐10‐6 Other descriptive name: RINGER'S SOLUTION Concentration unit: g/l gram(s)/litre Concentration type: equal Concentration number: 8,6‐ Trade Name: Syner‐KINASE Product Name: Syner‐KINASE Pharmaceutical Form: Powder for solution for injection/infusion INN or Proposed INN: Urokinase CAS Number: 9039‐53‐6 Other descriptive name: UROKINASE Concentration unit: IU international unit(s) Concentration type: CONDITION: Aneurysmal Subarachnoid Hemorrhage (aSAH) ; MedDRA version: 20.1 Level: LLT Classification code 10042320 Term: Subarachnoid hemorrhage System Organ Class: 100000004852 Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: ; Primary end point(s): Neurological outcome: Proportion of subjects with a favorable outcome measured on the modified Rankin Scale (mRS) at 6months after aSAH, assessed by an independent physician. mRS will be analyzed in a dichotomized fashion:; favorable, defined as: mRS 0‐3 (independent); vs.; unfavorable, defined as: mRS 4‐6 (dependent/dead); Main Objective: To assess whether cisternal lavage therapy with Urokinase, Ringer's solution and Nimodipine administered via a stereotactically implanted catheter into the prepontine cistern (IT, Investigational Treatment) improves neurological outcome and is safe in patients with aSAH. Secondary Objective: To assess whether cisternal lavage therapy with Urokinase and Nimodipine administered via a stereotactically implanted catheter into the prepontine cistern (IT, Investigational Treatment) improves neurological outcome and is safe in patients with aSAH. Timepoint(s) of evaluation of this end point: 6 months after aSAH INCLUSION CRITERIA: 1. Male or female patients aged =18 years and <80 years 2. Modified Fisher grade 3 or 42 3. Cisternal/Ventricular blood amount according to Hijdra Score = 203 4. Admission WFNS grade = 3 (if grade 5 only with fixed dilated pupil due to raised ICP for less than 45 minutes) 5. External ventricular drain (EVD) in situ or indication for placement of EVD 6. Disease duration =96 hours before randomization 7. Written informed consent, either by patient or by patient’s legally authorized representative 8. Cerebral aneurysm as definitive source of subarachnoid hemorrhage 9. Patients in whom the cerebral aneurysm has been safely treated via open surgical or endovascular technique. Are the trial subjects under 18? no Number of subjects for this age range: SECONDARY OUTCOME: ; Secondary end point(s): ‐ Neuropsychological outcome at 6 months following aSAH; ‐‐ Cognitive performance (Montreal Cognitive Assessment); ‐‐ Health‐related quality of life (SF‐36); ‐‐ Fatigue, anxiety and depressive symptoms (Frontal Systems Behavior Scale, Multidimensional Assessment of Fatigue, Hospital Anxiety and Depression Scale), Post‐traumatic stress disorder (Impact of Event Scale – R); ‐‐ Return‐to‐work parameters at 6 months; ‐ Rate and severity of delayed cerebral infarction (DCI) according to the Vergouwen criteria; ‐ Rate of delayed ischemic neurological deficit (DIND), defined as clinical deterioration caused by delayed cerebral ischemia (i.e. a new focal neurological deficit or decline on the Glasgow Coma Scale of 1 point not attributable to other causes) on days 3 – 21. (Note: The date of aSAH occurrence is defined as day 0.); ‐ Delta mean flow velocities of both middle cerebral arteries – measured by transcranial Doppler‐ultrasonography on days 3 – 21.; ‐ NIHSS score at days 3‐21 and at 6 months; ‐ Rates of shunt‐dependent hydrocephalus at 6 months following aSAH; ‐ Rate of endovascular interventions for the treatment of cerebral vasospasm; ‐ Key parameters of intensive care medicine (Sequential Organ Failure Score); ‐ Key parameters of endocrinological dysfunction; ‐ Morphological brain damage at 6 months after aSAH as assessed by MRI; ‐ Key markers of neuronal injury and systemic inflammation in patient blood; ‐ electroencephalographic patterns as measured by continuous EEG‐monitoring during intensive care period (exploratory endpoint); ‐ Safety of IT: (Serious) Adverse Events related to the IT; Timepoint(s) of evaluation of this end point: Timepoints of evaluations are included in the description of the respective endpoints