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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical Center - University Of Freiburg

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

17 May 2019 → ongoing

Decision date (initial)

2024-11-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Else Kröner-Fresenius-Stiftung

External identifiers

EU CT number

2024-517798-25-00

EudraCT number

2017-000868-15

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

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 objectives 1

1. 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.

Conditions and MedDRA coding

Aneurysmal Subarachnoid Hemorrhage (aSAH)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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) XML File Identifier: 1QQAfUUsgOy4U/EmSL6g0y1IS/g= Page 18/31 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.
2. 2. Modified Fisher grade 3 or 42
3. 3. Cisternal/Ventricular blood amount according to Hijdra Score ≥ 20
4. 4. Admission WFNS grade 1-5 (if grade 5 only with fixed dilated pupil due to raised ICP for less than 45 minutes)
5. 5. External ventricular drain (EVD) in situ or indication for placement of EVD
6. 6. Disease duration ≤96 hours before randomization
7. 7. Written informed consent, either by patient or by patient's legally authorized representative
8. 8. Cerebral aneurysm as definitive source of subarachnoid hemorrhage
9. 9. Patients in whom the cerebral aneurysm has been safely treated via open surgical or endovascular technique.

Exclusion criteria 12

1. 1. Pregnancy
2. 2. Surgical contraindications according to the opinion of the investigator
3. 3. Inability to administer study medication (known allergy to urokinase or nimodipine)
4. 4. Presence of a severe illness prior to aSAH (e.g. progressive cancer, terminal organ failure, severe neurological disorder, life expectancy < 1 year)
5. 5. Known and persistent abuse of medication or drugs
6. 6. Presence of severe cerebral infarction related to the aSAH or medical procedures prior to randomization
7. 7. Presence of intracerebral hematoma that is ≥ 30ml (assessed using the AxBxC/2 method)5 or in eloquent location prior to randomization
8. 8. Presence of a condition or abnormality that in the opinion of the Investigator would compromise safety of the patient
9. 9. Known severe complications during aneurysm securing (e.g. dissections of blood vessels, vessel occlusions, re-hemorrhage)
10. 10. Clinical signs of brain stem / midbrain compression (dilated pupil not reacting to light) persisting for more than 45 minutes at any time between aSAH onset and randomization
11. 11. Persons who are in a relationship of dependence/employment with the sponsor or the investigator
12. 12. For MRI follow-up: cardiac pacemaker and/or cardiac defibrillator. Stent implantation within the last 6 weeks prior to MRI, claustrophobia

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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)

Secondary endpoints 13

1. 1. mRS at 12 months after aSAH
2. 2. Neuropsychological outcome a)Neuropsychological outcome b) Health-related quality of life (SF-36) at 6 months c) 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) at 6 months d) Return-to-work parameters at 6 and 12 months
3. 3. Rate and severity of delayed cerebral infarction (DCI) according to the Vergouwen criteria
4. 4. 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.)
5. 5. Delta mean flow velocities of both middle cerebral arteries – measured by transcranial Doppler-ultrasonography on days 3 – 15.
6. 6. NIHSS score at day 32 and at 6 months
7. 7. Rates of shunt-dependent hydrocephalus at 6 months following aSAH
8. 8. Rate of endovascular interventions for the treatment of cerebral vasospasm
9. 9. Key parameters of endocrinological dysfunction
10. 10. Morphological brain damage at 6 months after aSAH as assessed by MRI
11. 11. Key markers of neuronal injury and systemic inflammation in patient blood
12. 12. electroencephalographic patterns as measured by continuous EEGmonitoring during intensive care period (exploratory endpoint)
13. 13. Safety of IT: (Serious) Adverse Events related to the IT

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical Center - University Of Freiburg

Sponsor organisation

Medical Center - University Of Freiburg

Address

Breisacher Strasse 153, Mooswald Mooswald

City

Freiburg Im Breisgau

Postcode

79110

Country

Germany

Scientific contact point

Organisation

Medical Center - University Of Freiburg

Contact name

Roland Roelz

Public contact point

Organisation

Medical Center - University Of Freiburg

Contact name

Cedric Cedric Bradbury

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications