Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Efficacy and Safety of Clazosentan in Reducing Vasospasm-related Morbidity and All-cause Mortality in Adult Patients With Aneurysmal Subarachnoid Hemorrhage Treated by Surgical Clipping.
Brief Summary: The aim of this study is to demonstrate that clazosentan, administered as a continuous intravenous infusion at 5 mg/h until Day 14 post aneurysmal subarachnoid hemorrhage (aSAH), reduces the incidence of cerebral vasospasm -related morbidity and all-cause mortality within 6 weeks post-aSAH treated by surgical clipping. The primary endpoint of the study is the occurrence of cerebral vasospasm-related morbidity, and mortality of all-causes within 6 weeks post-aSAH, defined by at least one of the following:

1. Death (all causes).
2. New cerebral infarct(s) due to cerebral vasospasm as either the primary or relevant contributing cause, or not adjudicated to be entirely due to causes other than vasospasm.
3. Delayed ischemic neurological deficit (DIND) due to cerebral vasospasm as either the primary or relevant contributing cause, or not adjudicated to be entirely due to causes other than vasospasm.
4. Neurological signs or symptoms (depending on state of consciousness), in the presence of confirmed cerebral vasospasm on angiography (DSA or CTA), leading to the administration of a valid rescue therapy.

An independent Critical Events Committee (CEC) will adjudicate whether or not patients meet the primary endpoint and its individual morbidity components.


Options:
A: Inclusion Criteria:

1. Males and females aged 18 to 75 years (inclusive).
2. Patients with a ruptured saccular aneurysm, confirmed by angiography (digital subtraction angiography \[DSA\] or computed tomography angiography \[CTA\]), and which has been successfully secured by surgical clipping. The time of aneurysm rupture must be known or possible to estimate with a reasonable degree of certainty.
3. World Federation of Neurological Surgeons (WFNS) grade I-IV measured prior to the clipping procedure, and which does not worsen to grade V post-procedure (based on regular Glasgow Coma Scale \[GCS\])\*
4. Patients with any diffuse clot (long axis \> or = 20 mm, or any clot present across both hemispheres) on baseline CT scan.
5. Women of childbearing potential must have a negative serum pregnancy test and must use a reliable method of contraception during the 12 weeks following study drug discontinuation.
6. Written informed consent to participate in the study must be obtained from the patient or a legal representative prior to initiation of any study-mandated procedure and randomization.

   * Patients must be evaluable for WFNS grade prior to the clipping procedure. Patients who cannot be assessed for WFNS post-procedure due to a requirement for uninterrupted sedation (e.g., for high or unstable intracranial pressure \[ICP\]) may be included in the study provided that a CT scan is performed at 12 hours post-procedure, but prior to randomization, ruling out any large procedure-related infarct.

Exclusion Criteria:

1. Patients with subarachnoid hemorrhage (SAH) due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or mycotic aneurysms).
2. Patients with intraventricular or intracerebral blood, in the absence of subarachnoid blood, or with only a local clot.
3. Presence of cerebral vasospasm seen on angiography prior to the clipping procedure.
4. Patients who experienced a major complication during the clipping procedure, such as massive bleeding, major arterial occlusion, a large territorial cerebral infarct defined as involving \> 1/3 of a vascular territory, or a new major neurological deficit post-procedure (e.g., hemiplegia or aphasia lasting \> or = 12 hours post-aneurysm clipping).\*
5. Patients for whom study drug cannot be started within 56 hours after the aneurysm rupture.
6. Patients who have had their aneurysm secured by coiling only.
7. Patients for whom it is known, at the time of screening, that certain follow-up, protocol-mandated imaging assessments will not be feasible.
8. Patients with hypotension (systolic blood pressure (SBP)\< or = 90 mmHg) that is refractory to treatment.
9. Patients with aspiration pneumonia.
10. Patients with pulmonary edema or severe cardiac failure requiring inotropic support.
11. Any severe or unstable concomitant condition or disease (e.g., known significant neurological deficit, cancer, hematological, or coronary disease), or chronic condition (e.g., psychiatric disorder), which, in the opinion of the investigator, would affect the assessment of the safety or efficacy of the study drug.
12. Significant kidney and/or liver disease, as defined by plasma creatinine \> or = 2.5 mg/dL (221 micromol/l) and/or total bilirubin \> 3 mg/dL (51.3 micromol/l) measured at the local site laboratory.
13. Patients receiving i.v. nimodipine, i.v. nicardipine, or fasudil hydrochloride, must have these drugs discontinued at least 4 hours prior to initiation of the study treatment.
14. Patients receiving statins for less than 2 weeks prior to admission must have them discontinued prior to study drug initiation.
15. Patients receiving cyclosporin A or other calcineurin inhibitors (e.g., tacrolimus), or patients for whom it is known at the time of randomization that these medications will be started during the study drug infusion period.
16. Patients who have received an investigational product within 28 days prior to randomization or those who have already participated in the current study.
17. Patients unlikely to comply with the protocol (e.g., unable to return for follow-up visits).
18. Known hypersensitivity to other endothelin receptor antagonists.
19. Patients with current alcohol or drug abuse or dependence.

    * Further detail on exclusion criterion number 4:

      * "Large territorial infarct" refers to those infarcts detected during the clipping procedure or immediately post-procedure (i.e., CT performed for suspicion of cerebral infarct or other complication). This does not imply having to wait 24-48 hours post-procedure to perform the protocol-mandated CT scan in order to randomize a patient.
      * Evaluation for a new major neurological deficit post-procedure implies the reversal of sedation (or waiting for the patient to recover from sedation) and the performance of a GCS examination (verbal scores in intubated patients may be extrapolated from the eye-opening and motor scores using the values provided in the table included in Section 3.9.1.2.1 of the protocol). In the event of a new major neurological deficit that does not improve within 12 hours after the clipping procedure, the patient cannot be included in the study.
B: Inclusion Criteria:

* Age 18 years or older
* IV nicardipine can be initiated within 4.5 hours of symptom onset.
* Clinical signs consistent with the diagnosis of stroke, including impairment of language, motor function, cognition, and/or gaze, vision, or neglect.
* Total Glasgow Coma Scale (GCS) score (aggregate of verbal, eye, and motor response scores) of 5 or greater at time of emergency department (ED) arrival.
* International normalized ratio (INR) value \< 1.5
* CT scan demonstrates intraparenchymal hematoma with manual hematoma volume measurement \<60 cc.
* For subjects randomized prior to IV antihypertensive administration: SBP greater than 180 mmHg\* prior to IV antihypertensive treatment (this includes pre-hospital treatment) AND WITHOUT spontaneous SBP reduction to below 180 mmHg at the time of randomization OR
* For subjects randomized after IV antihypertensive administration: SBP greater than 180 mmHg\* prior to IV antihypertensive treatment (this includes pre-hospital treatment) AND WITHOUT SBP reduction to below 140 mmHg at the time of randomization.
* Informed consent obtained by subject, legally authorized representative, or next of kin.

  * Notes: The unit "mmHg" stands for "millimeters of mercury", a standard way of measuring blood pressure. Patients with SBP \< 180 mmHg should be monitored for 4.5 hours from symptom onset as their SBP may rise to eligible levels before the eligibility window closes.

Exclusion Criteria:

* ICH is due to previously known neoplasms, arteriovenous malformation (AVM), or aneurysms.
* Intracerebral hematoma considered to be related to trauma.
* ICH located in infratentorial regions such as pons or cerebellum.
* Intraventricular hemorrhage (IVH) associated with intraparenchymal hemorrhage and blood completely fills one lateral ventricle or more than half of both ventricles.
* Patient to receive immediate surgical evacuation.
* Current pregnancy, or parturition within previous 30 days, or active lactation.
* Use of dabigatran within the last 48 hours\*\*.
* A platelet count less than 50,000 per microliter (µL or mm3)
* Known sensitivity to nicardipine.
* Pre-morbid disability requiring assistance in ambulation or activities of daily living.
* Subject's living will precludes aggressive ICU management.
* Subject is currently participating in another interventional clinical trial

  * Use of dabigatran was clarified through investigator presentations, educational materials, and clinical tools to include newer similar class medications (such as rivaroxaban, apixaban, and edoxaban) that were being developed and in various stages of approval across enrolling countries through the course of this trial, in the event that patients using these medications may have been encountered during screening.
C: Inclusion Criteria:

* Aged 18 years or above
* Acute stroke due to spontaneous ICH confirmed by clinical history \& CT scan
* At least 2 systolic BP measurements of \>/=150mmHg and \</=220mmHg, recorded 2 or more minutes apart
* Able to commence randomly assigned BP lowering regimen within 6 hours of stroke onset
* Able to be actively treated and admitted to a monitored facility e.g. HDU/ICU/acute stroke unit

Exclusion Criteria:

* Known definite contraindication to an intensive BP lowering regimen
* Known definite indication for intensive BP lowering regimen as (or more) intensive than the active treatment arm
* Definite evidence that the ICH is secondary to a structural abnormality in the brain
* Previous ischaemic stroke within 30 days
* A very high likelihood that the patient will die within the next 24 hours on the basis of clinical and/or radiological criteria
* Known advanced dementia or significant pre-stroke disability
* Concomitant medical illness that would interfere with outcome assessments and follow up
* Already booked for surgical evacuation of haematoma
* Previous participation in this trial or current participation in another investigational drug trial
* A high likelihood that the patient will not adhere to the study treatment and follow up regimen
D: Inclusion Criteria:

* Clinical stroke syndrome with limb paresis, not likely to represent a transient ischaemic attack or non-stroke pathology (e.g. cerebral tumour)
* Systolic blood pressure ≥ 140 mm Hg
* Trial treatment possible within 30 hrs of symptom onset. If time of onset is not known, use the time when the patient was last known to be well.
* Consent (subsidiary, assent from legal acceptable representative, or waiver of consent)
* Age \>18 years

Exclusion Criteria:

* Markedly reduced consciousness (i.e. Scandinavian Stroke Scale consciousness score ≤ 2)
* Patient already receiving AT1 receptor blocker
* Contraindication to treatment with AT1 receptor blocker, e.g.:

  * known renal failure (women: creatinine ≥ 150 µmol/L; men: ≥ 180 µmol/L)
  * previously diagnosed bilateral renal artery stenosis
  * previously diagnosed high-grade aortic stenosis
  * previously diagnosed seriously impaired liver function and/or cholestasis
  * known intolerance to candesartan or other tablet ingredients
* Clear indication, in the clinician's view, for start of treatment with AT1 receptor blocker during the treatment period (e.g. chronic heart failure grade III-IV, in the presence of intolerance to ACE inhibitors)
* Clear indication, in the clinician's view, for antihypertensive therapy during the acute phase of stroke (i.e. concurrent hypertensive encephalopathy or aortic dissection, or other situations)
* Other serious or life-threatening disease before the stroke:
* Patient severely mentally or physically disabled (e.g. Mini Mental Status score \< 20, or modified Rankin Scale score ≥ 4)
* Life expectancy \< 12 months
* Patient unavailable for follow-up (e.g. no fixed address)
* Pregnant or breast-feeding woman

Answer: A