Table 4 Modification of investigational treatment

Procedure-related undesired effect, i.e., attributable to physical/mechanical effects of intrathecal fluid application

Reduction of infusion rate while maintaining the doses of the IMPs.

Undesired effect that is potentially attributable to pharmacological effects of urokinase or nimodipine

Reduction in doses of these drugs or lavage with Ringer’s solution only.

Occurrence of intracranial hemorrhage after stereotactic catheter implantation and administration of IMP

• Evaluation of whether hemorrhage is related to IMP administration, related to the application procedure, or due to other causes (e.g., due to aneurysm re-bleed, secondary aneurysm rupture, surgical procedures, hemorrhagic transformation of cerebral infarction, spontaneous).

• Termination of urokinase and nimodipine if administration of these IMPs is the most likely cause of intracranial hemorrhage. It will not be recommenced until deemed safe by the investigator.

• Lavage with Ringer’s solution only if deemed safe by the investigator.

• If relatedness to IMPs considered unlikely by the investigator: evaluation of potential benefits and risks of continuation of the IMPs; continued administration of IMPs if benefits of continuation are assumed to outweigh the risks.

Occurrence of raised intracranial pressure (ICP > 20 mmHg)

If considered related to IT administration: termination until normalization of ICP; continued administration of IMPs if deemed safe by the investigator.

Occurrence of cardiac symptoms (e.g., brady- or tachycardia, arrhythmias, electrocardiographic abnormities)

• If graded as serious and if potentially induced by the IT, administration of the IMPs is paused immediately and may be continued with or without dose modifications and changes in infusion rates.

• If graded as non-serious but related to the IT: continuation of IT with dose modifications and/or changes in infusion rates.

Occurrence of headache

Reduction of IMP doses and/or infusion rates if considered attributable to the IT.

Normal route of lavage (intracranial infusion via the cisternal STX-VCS catheter and outflow via the EVD) not possible, e.g., due to impaired outflow

Reversed flow direction (i.e., EVD in, cisternal catheter out).

Lavage therapy not feasible at the intended infusion rate

Lower infusion rate or small volume bolus lavage therapy.

Particular clinical circumstances (e.g., recurrent intracranial hemorrhage, persisting intraventricular/intracerebral/subarachnoid blood clots, refractory cerebral vasospasm, cerebral vasospasm lasting beyond day 21)

Recommencement and/or dose modifications of intrathecally administered urokinase or nimodipine.