REACT: Prevention and Treatment of Vasospasm with Clazosentan
Supported by: Idorsia Pharmaceuticals Ltd
Principal Investigator at BMC: Thanh Nguyen, MD
Primary Research Contact: Katie Dam, BA (617-638-9004)
Summary
A prospective, multi-center, double-blind, randomized, placebo-controlled, parallel-group, Phase 3 study to assess the efficacy and safety of clazosentan in preventing clinical deterioration due to delayed cerebral ischemia (DCI), in adult subjects with aneurysmal subarachnoid hemorrhage (aSAH).
In previous and currently ongoing clinical research studies, clazosentan has already been safely administered to more than 1500 subjects with aneurysmal subarachnoid hemorrhage. The available information suggests that clazosentan can prevent a number of medical complications related to vasospasm (narrowing of blood vessels). Clazosentan also shows the potential to reverse vasospasm if initiated early enough. Despite the information already collected from previous research, the present study is being conducted to confirm the effectiveness of clazosentan in a group of subjects that is expected to benefit the most from treatment with it. In this study, clazosentan is being tested against normal routine medical care to determine if clazosentan can reduce the risk of developing complications related to vasospasm and permanent brain damage. The side effects of clazosentan will also be evaluated.
Enrollment Criteria
Inclusion Criteria:
For inclusion in the study, the subject must fulfill all of the following inclusion criteria. It is not permitted to waive any of the criteria for any subject.
- 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.
- Subjects 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 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.
- Subjects must meet one of the two following inclusion criteria:
- High-risk prevention: Subjects with a “thick and diffuse clot” 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 following the time of aneurysm rupture.
- OR
- Early treatment: Subjects 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.
- High-risk prevention: Subjects with a “thick and diffuse clot” 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 following the time of aneurysm rupture.
- Presence of a cerebral CT scan, performed at least 8 hours post-aneurysm-securing procedure and within 24 hours prior to randomization, which rules out a significant (e.g., symptomatic) new or worsened cerebral infarct or re-bleeding of the repaired aneurysm, associated with clinical symptoms.
- A woman of childbearing potential is eligible only if the serum pregnancy test performed during the screening period is negative. If breastfeeding, agreement must be obtained to refrain from breastfeeding for the duration of the treatment.
Exclusion Criteria:
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to waive any of the criteria for any subject.
aSAH, aneurysm-securing procedure, vasospasm
- Subjects 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).
- Subjects 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, intracerebral 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.
- IVH on the hospital admission CT scan, filling more than 50% of both lateral ventricles and with involvement of the 3rd and 4th ventricles.
- Intra-cerebral 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
- Subjects 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.
- Subject 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.
- Subjects with a GCS score of ≤9 at the time of randomization and without intracranial pressure (ICP) monitoring.
- Modified Rankin Scale (mRS) score of 3 or higher, prior to the aSAH (i.e., due to a chronic condition).
Other clinical considerations
- Subjects with total bilirubin >2 x 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 [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 randomization.
Medications and therapies
- Lumbar and/or cisternal drainage performed specifically to prevent or treat cerebral vasospasm at any time from hospital admission to randomization.
- Prophylactic or therapeutic administration of intra-arterial vasodilators or ozagrel, or performance of cerebral angioplasty at any time from hospital admission to randomization.
- Subjects for whom at the time of randomization administration of urgent rescue therapy (i.e., cerebral angioplasty, intra-arterial/intrathecal/intra-cisternal/intra-ventricular administration of vasodilators or ozagrel) is anticipated.
- Use of intrathecal, intra-cisternal, or intra-ventricular thrombolytics at any time from hospital admission to randomization.
- Administration of intrathecal, intra-cisternal, and intra-ventricular vasodilators (e.g., nimodipine), i.v. nicardipine, or i.v. milrinone, within 4 hours prior to randomization.
- Administration of i.v. fasudil or i.v. ozagrel within 24 hours prior to randomization.
- Use of intra-aortic balloon counter-pulsation devices at any time form hospital admission to randomization.
- Use at any time from hospital admission to randomization, or any investigational drugs, procedures or devices, including:
- Investigational clipping material and investigational coiling material such as liquid embolic material, stents or flow diverting devices, and,
- Any other medical administered to prevent or treat vasospasm, reduce ischemic complications, or to improve clinical outcome post aSAH, that has not been approved for these specific indications by local health authorities (e.g., new post-hospital admission prescription of “statins,” therapeutic hypothermia).
- Subjects receiving strong inhibitors of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 transporter proteins (e.g., cyclosporine A, rifampin, lopinavir/ritonavir), or subjects for whom it is likely at the time of randomization that these medications will be started during the study treatment infusion period.
- Known hypersensitivity to clazosentan or any excipient in the formulation.
Status: Actively enrolling patients