Clinical Research Study With Clazosentan to Evaluate Its Effects on Preventing Complications Due to the Narrowing of the Blood Vessels (Vasospasm) in the Brain, Caused by Bleeding Onto the Surface of the Brain
Condition: Aneurysmal Subarachnoid Hemorrhage
MeSH terms: Subarachnoid Hemorrhage; Hemorrhage
Intervention: Clazosentan; Placebo
Intervention description: Clazosentan will be administered as a continuous intravenous infusion at the dose of 15 mg/hour for up to 14 days.; Placebo will be administered at the same infusion rate as clazosentan for up to 14 days.
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: This study will be performed in a double-blind fashion. The investigator, study personnel, subjects, clinical research associates (CRAs), sponsor personnel, and vendor / Contract Research Organization (CRO) personnel involved in the conduct of the study will remain blinded to the study treatment received by the subjects during the double-blind treatment period until study closure
Enrollment: 409.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This study will evaluate if clazosentan (on top of normal routine medical care) can reduce
      the risk of developing complications related to cerebral vasospasm and permanent brain damage
      as compared to normal routine medical care alone.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent to participate in the study must be obtained from the subject
             or proxy/legal representative at any time from hospital admission to prior to
             initiation of any study-mandated procedure,

          -  Males and females aged 18 to 70 years (inclusive, at hospital admission),

          -  Participants with a ruptured saccular aneurysm, angiographically confirmed by DSA or
             CTA, which has been successfully secured within 72 hours of rupture, by surgical
             clipping or endovascular coiling,

          -  WFNS (World Federation of Neurosurgical Societies) grades 1-4 (based on Glasgow Coma
             Scale [GCS]) assessed after recovery from the aneurysm-securing procedure and after
             external ventricular drainage for hydrocephalus, if required.

          -  Participants must meet the criteria for the high-risk prevention group: Subjects with
             a "thick and diffuse clot" (thick and diffuse is defined as a thick confluent clot,
             more than 4 mm in thickness, involving 3 or more basal cisterns) on the hospital
             admission CT scan, absence of cerebral vasospasm at the time of randomization, and
             possibility to start study drug in the ICU (or equivalent environment where all
             protocol assessments can be performed and the Patient Management Guidelines followed),
             within 96 hours after the time of the aneurysm rupture.

          -  The recruitment into the early treatment group, i.e. participants without a thick and
             diffuse clot on the hospital admission CT scan who develop asymptomatic or minimally
             symptomatic moderate to severe angiographic vasospasm, within the 14-day period
             post-aneurysm rupture, and for whom it is possible to start study drug in the ICU (or
             equivalent environment where all protocol assessments can be performed and the Patient
             Management Guidelines followed), within 24 hours of this angiographic diagnosis, has
             been discontinued.

          -  Presence of a cerebral CT scan performed at least 8 hours post aneurysm securing
             procedure and within 24 hours prior to randomization.

          -  Absence of a significant (e.g., symptomatic or large) new or worsened cerebral infarct
             or re-bleeding of the repaired aneurysm on the post-procedure CT scan.

          -  A woman of childbearing potential is eligible only if the pregnancy test performed
             during the screening period is negative. Agreement must be obtained to take the
             necessary precautions to avoid pregnancy from hospital discharge until 30 days
             post-study drug discontinuation. If breastfeeding, agreement must be obtained to
             refrain for the duration of the treatment with study drug and until 30 days post-study
             drug discontinuation.

          -  Males are eligible for study participation only if they agree to take the necessary
             precautions to avoid pregnancy in a female partner from hospital discharge until 30
             days post-study drug discontinuation.

        Exclusion Criteria:

          -  Aneurysmal subarachnoid hemorrhage (aSAH), aneurysm-securing procedure, vasospasm:

               -  Participants 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),

               -  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 peri-aneurysm 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 hospital admission CT scan, filling more than
                  50% of both lateral ventricles and with involvement of the 3rd and 4th
                  ventricles.

               -  Intracerebral hemorrhage on the hospital 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 subject is currently
                  hospitalized). Vasospasm occurring during the aneurysm securing procedure is not
                  an exclusion criterion,

          -  Neurological and functional status:

               -  Participants 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,

               -  Participants with a GCS score of ≤ 9 at the time of randomization and without
                  intracranial pressure (ICP) monitoring,

               -  Modified Rankin Score of 3 or higher, prior to the aSAH (i.e., due to a chronic
                  condition),

          -  Other clinical considerations:

               -  Participants with total bilirubin > 2 times the upper limit of normal, and/or a
                  known diagnosis or clinical suspicion of liver cirrhosis or moderate to severe
                  hepatic impairment,

               -  Hypotension (systolic blood pressure [SBP] ≤ 90 mmHg) at 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
                  subjects, defined as PaO2/FiO2 ≤ 200,

               -  High sustained ICP (> 25 mmHg lasting > 20 minutes) at time of randomization,
                  despite optimal treatment, in subjects with ICP monitoring,

               -  Severe cardiac failure requiring inotropic support at the time of random