Table 2 Exclusion criteria of the REACT trial

aSAH, aneurysm-securing procedure, vasospasm

- Patients with SAH due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or mycotic aneurysms, SAH associated with arterio-venous malformation, vertebral dissections).

- Patients with at least one unruptured aneurysm for whom a subsequent intervention is planned within 3 months of the aSAH.

- Significant bleeding post aneurysm-securing procedure (e.g., due to intra-ventricular drain, intra-cerebral hemorrhage, epidural hematoma, vessel dissection or rupture, re-bleeding of the repaired aneurysm), based on investigator judgment.

- Intra- or perianeurysm securing procedure complication, requiring non-routine medical or interventional treatment such as administration of an antithrombotic or anti-platelet agent (e.g., abciximab), which is not completely resolved prior to randomization.

- Intraventricular hemorrhage on the admission CT scan, filling more than 50% of both lateral ventricles and with involvement of the 3rd and 4th ventricles.

- Intracerebral hemorrhage on the admission CT scan with an approximate volume of > 50 mL.

- Presence of cerebral vasospasm at hospital admission (initial admission or transfer from another hospital) believed to be associated with a prior bleed (i.e., occurring before the bleed for which the patient is currently hospitalized). Vasospasm occurring during the aneurysm-securing procedure is not an exclusion criterion.

Neurological and functional status

- Patients with a new major neurological deficit occurring post aneurysm-securing procedure, which is attributable to the procedure and does not improve to pre-procedure status before randomization.

- Patients who are still under the influence of pharmacological sedation at the time of randomization or who are, for whatever reason, not evaluable for baseline and regular daily neurological assessments.

WFNS grade 5 (based on GCS) immediately prior to planned randomization, assessed after external ventricular drainage for hydrocephalus, if required.

- GCS score ≤ 9 at the time of randomization and without ICP monitoring

- mRS score ≥ 3 before the aSAH (i.e., due to a chronic condition).

Other clinical considerations

- Patients with total bilirubin > 2 × the upper limit of normal, and/or a known diagnosis or clinical suspicion of liver cirrhosis or moderate to severe hepatic impairment.

- Any concomitant condition or disease (including psychiatric and neurological conditions, drug abuse, severe alcoholism), which, in the opinion of the investigator, would affect the assessment of the safety or efficacy of the study treatment.

- Hypotension (systolic blood pressure ≤ 90 mmHg) at the time of randomization that is refractory to treatment.

- Unresolved pulmonary edema or significant pneumonia still present at the time of randomization, or severe hypoxia at the time of randomization in intubated patients defined as PaO₂/FiO₂ ≤ 200.

- High sustained ICP (> 25 mmHg lasting > 20 minutes) at the time of randomization, despite optimal treatment in patients with ICP monitoring.

- Severe cardiac failure requiring inotropic support at the time of randomization.

Medications and therapies

- Known hypersensitivity to clazosentan or any excipient in the formulation.

At any time from hospital admission to randomization:

- Lumbar and/or cisternal drainage performed specifically to prevent or treat cerebral vasospasm.

- Cerebral angioplasty or intra-arterial vasodilators.

- Intrathecal, intracisternal, or intraventricular thrombolytics.

- Intra-aortic balloon counter-pulsation devices.

- Investigational drugs, procedures or devices.

- Strong inhibitors of OATP1B1 and OATP1B3 transporter proteins (e.g., cyclosporin A, rifampicin, lopinavir/ritonavir).

Within 4 hours prior to randomization:

- Intrathecal, intracisternal, and intraventricular vasodilators (e.g., nimodipine), i.v. nicardipine (except for blood pressure control), or i.v. milrinone.

Anticipated at randomization:

- Urgent rescue therapy (i.e., cerebral angioplasty, intra-arterial/intrathecal/intracisternal/ intraventricular vasodilators).

- Strong inhibitors of OATP1B1 and OATP1B3 transporter proteins.