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
- Conditions
- Aneurysmal Subarachnoid Hemorrhage
- Interventions
- Drug: Placebo
- Registration Number
- NCT03585270
- Lead Sponsor
- Idorsia Pharmaceuticals Ltd.
- Brief 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.
- Detailed Description
When a blood vessel just outside the brain bursts and causes bleeding onto its surface, the space surrounding the brain (the subarachnoid space) fills with blood. This condition is called subarachnoid hemorrhage. The bleeding due to the rupture of a pouch-like structure or a bulge (called an aneurysm) that formed on one of the blood vessels is condition called aneurysmal subarachnoid hemorrhage (aSAH).
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.
Participation will last for approximately 6 months from the episode of bleeding. For subjects randomized in the high-risk prevention group, treatment will start within 96 hours following the time of the aneurysm rupture, and be administered where possible, for 14 days. For subjects randomized in the early treatment group, treatment must begin within 24 hours of the time of the angiogram documenting the cerebral vasospasm necessary for entry into the study. Treatment will be administered for a minimum of 6 days and a maximum of 14 days. Recruitment in the early treatment group has been discontinued.
The end-of-study will be conducted as a telephone interview 6 months after the episode of bleeding.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 409
- 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.
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Participants will receive clazosentan matching-placebo for up to 14 days, followed by a safety follow-up period of 24 hours, and an extended follow-up period to the end-of-study visit at Week 24 post aneurysmal subarachnoid hemorrhage (aSAH). Clazosentan Clazosentan Participants will receive clazosentan for up to 14 days, followed by a safety follow-up period of 24 hours, and an extended follow-up period to the end-of-study visit at Week 24 post aneurysmal subarachnoid hemorrhage (aSAH).
- Primary Outcome Measures
Name Time Method Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation Up to 14 days post-study drug initiation Clinical deterioration due to delayed cerebral ischemia is defined as a worsening of at least 2 points compared to the reference score, on the modified Glasgow Coma Scale or the abbreviated National Institutes of Health Stroke Scale (aNIHSS), lasting for at least 2 hours, which cannot be entirely attributed to causes other than cerebral vasospasm. It is centrally adjudicated by the Clinical Event Committee (CEC) based on a written charter and review of clinical data, case narratives, angiograms and Computed Tomography scans.
- Secondary Outcome Measures
Name Time Method Occurrence of Clinically Relevant Cerebral Infarction at Day 16 Post-study Drug Initiation At Day 16 post study drug initiation A clinical relevant cerebral infarction was defined as: all-cause cerebral infraction greater than or equal to 5 cm\^3 or cerebral infarction less than 5 cm\^3 in participants with clinical deterioration due to delayed cerebral ischemia.
Cerebral infarction refers to new or worsened infarcts and was determined by a central radiology review comparing the total volume of infarcts on the computed tomography (CT) scan performed 16 days after study drug initiation with the total volume on the CT scan performed just prior to randomization.Long-term Clinical Outcome Assessed by the Glasgow Outcome Scale Extended (GOSE) at Week 12 Post-aSAH At Week 12 post-aneurysmal subarachnoid hemorrhage (aSAH) The Glasgow Outcome Scale - Extended (GOSE) is a scale scored by the physician. The GOSE scores range from 1 (dead) to 8 (upper good recovery).
The long-term clinical outcome assessed by the GOSE was dichotomized into poor outcome (score ≤ 4) and good outcome (score \> 4)Long-term Clinical Outcome Assessed by the Modified Rankin Scale (mRS) at Week 12 Post-aneurysmal Subarachnoid Hemorrhage (aSAH) At Week 12 post-aneurysmal subarachnoid hemorrhage (aSAH) The modified Rankin Scale (mRS) was used to measure the degree of disability in participants who had a ruptured saccular aneurysm and were at a high risk of developing a delayed cerebral infarction (DCI). The mRS is scored by the physician. The mRS scores ranged from 0 (no symptoms) to 6 (dead). The mRS score was dichotomized into poor outcome (score greater and equal to 3) and good outcome (score less than 3).
Trial Locations
- Locations (80)
University of Illinois - Department of Neurosurgery
🇺🇸Chicago, Illinois, United States
University Hospitals Case Medical Center - Department of Neurosurgery
🇺🇸Cleveland, Ohio, United States
Debreceni Egyetem, Idegsebészet
🇭🇺Debrecen, Hungary
Pécsi Tudományegyetem Klinikai Központ, Idegsebészeti Klinika
🇭🇺Pécs, Hungary
Turku University Hospital Neurosurgery, T-hospital
🇫🇮Turku, Finland
Rambam Healthcare Campus, Neurology Department
🇮🇱Haifa, Israel
Royal University Hospital Department of Neurology
🇨🇦Saskatoon, Saskatchewan, Canada
Helsingin yliopistollinen keskussairaala Neurokirurgian klinikka
🇫🇮Helsinki, Finland
Tampereen yliopistollinen sairaala Neurokirurgian klinika
🇫🇮Tampere, Finland
Halifax Infirmary, Nova Scotia Health Authority
🇨🇦Halifax, Nova Scotia, Canada
Medizinische Universität Innsbruck; Universitätsklinik für Neurologie und Psychiatrie
🇦🇹Innsbruck, Austria
Kepler Universitätsklinikum, Universitätsklinik für Neurochirurgie
🇦🇹Linz, Austria
Hospital - Cliniques Universitaires Saint-Luc, Service de Neurochirurgie
🇧🇪Brussels, Belgium
Neurology Department, University Hospital
🇧🇪Gent, Belgium
Vanderbilt University Medical Center - Department of Neurosurgery
🇺🇸Nashville, Tennessee, United States
University of Alberta Hospital Department of Neurological Surgery
🇨🇦Edmonton, Alberta, Canada
Oddział Neurochirurgii i Neurotraumatologii z Pododdziałem Leczenia Chorób Naczyniowych Centralnego Układu Nerwowego
🇵🇱Poznań, Poland
University Hospital in Pilsen, Department of Neurosurgery
🇨🇿Plzen, Czechia
Ústřední vojenská nemocnice Praha Neurochirurgická klinika
🇨🇿Praha, Czechia
Northwell Health, Department of Neurosurgery
🇺🇸Manhasset, New York, United States
Azienda Ospedaliera Padova-Università degli Studi di Padova - Istituto di Anestesia e Rianimazione
🇮🇹Padova, Italy
Fondazione Policlinico Universitario Agostino Gemelli Università Cattolica del Sacro Cuore, UOS Terapia Intensiva Neurochirurgic
🇮🇹Rome, Italy
Boston University School of Medicine / Boston University Medical Center
🇺🇸Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center Dept of Neurosurgery
🇺🇸Boston, Massachusetts, United States
Mt Sinai Hospital
🇺🇸New York, New York, United States
Oklahoma University Health Sciences Center - Department of Neurology
🇺🇸Oklahoma City, Oklahoma, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Penn State Milton S Hershey Medical Center, Neurosurgery
🇺🇸Hershey, Pennsylvania, United States
Hospital Erasme, Service de Soins Intensifs
🇧🇪Brussels, Belgium
Winnipeg Regional Health Authority Health Sciences Centre
🇨🇦Winnipeg, Manitoba, Canada
Fakultní nemocnice Brno Neurochirurgická klinika
🇨🇿Brno, Czechia
Masarykova nemocnice v Ústí nad Labem Neurochirurgie
🇨🇿Ústí Nad Labem, Czechia
Odense Universitets Hospital Neurokirurgisk afdelning
🇩🇰Odense, Denmark
Kuopio University Hospital
🇫🇮Kuopio, Finland
Hôpital neurologique Pierre Wertheimer Service de Reanimation
🇫🇷Bron, France
Hôpital de la Timone 2, Intensive Care Unit SAR 1
🇫🇷Marseille, France
Hôpital Gabriel Montpied, ICU DEPT, Neuro reanimation departement
🇫🇷Clermont-Ferrand, France
Hôpital Nord Laennec - CHU de Nantes
🇫🇷Nantes, France
Charite Universitätsmedizin Berlin - Klinik und Poliklinik für Neurochirurgie
🇩🇪Berlin, Germany
Hôpital Pitié-Salpêtrière, Service de neuroréanimation chirurgicale Babinski
🇫🇷Paris, France
University of Erlangen-Nürnberg, Dpt. of Neurosurgery
🇩🇪Erlangen, Germany
Hospital Lariboisiere Paris
🇫🇷Paris, France
Univ Hosp Toulouse, University Hospital Purpan Pierre Paul Riquet Hospital
🇫🇷Toulouse, France
Klinik für Diagnostische Radiologie und Neuroradiologie, Augsburg
🇩🇪Augsburg, Germany
University Hospital of Essen, Department of Neurosurgery
🇩🇪Essen, Germany
Universitätsklinik Frankfurt, Klinik und Poliklinik für Neurochirurgie, Dept of neurosurgery
🇩🇪Frankfurt, Germany
Bezirkskrankenhaus Günzburg - Klinik für Neurochirugie
🇩🇪Günzburg, Germany
Asklepios Klinik St. Georg - Neurochirugie
🇩🇪Hamburg, Germany
University Hospital of Hamburg-Eppendorf, Dpt. of Neurosurgery
🇩🇪Hamburg, Germany
Universitätsklinikum Rostock, Abteilung für Neurochirurgie
🇩🇪Rostock, Germany
Beilinson Hospital, Rabin Medical Center, Department of Neurosurgery
🇮🇱Petah tikva, Israel
Neurochirurgische Universitätklinik des Heidelberg, Dept of Neurosurgery
🇩🇪Heidelberg, Germany
University Regensburg, Dpt. of Neurosurgery
🇩🇪Regensburg, Germany
Hadassah Medical Center
🇮🇱Jerusalem, Israel
ASST Monza, Hospital San Gerardo, TERAPIA INTENSIVA Neurochirurgica
🇮🇹Monza, Italy
The Chaim Sheba Medical Centre - Neurosurgery
🇮🇱Ramat Gan, Israel
Hospital Vall d'Hebron Departamento Neuroradiología
🇪🇸Barcelona, Spain
Katedra i Klinika Neurochirurgii Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie
🇵🇱Warszawa, Poland
Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego
🇵🇱Łódź, Poland
University Hospital of Gran Canaria Dr. Negrin
🇪🇸Las Palmas De Gran Canaria, Spain
Hospital Universitario Germans Trias i Pujol - Neurology Department
🇪🇸Badalona, Spain
Hospital Universitari de Bellvitge
🇪🇸Hospitalet de Llobregat, Spain
Hospital Clinic Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario 12 de Octubre, Departamento Neurosurgery Division Neuroradiology
🇪🇸Madrid, Spain
Sahlgrenska Universitetssjukhuset, Verksamheten för neurokirurgi, Neurosjukvården
🇸🇪Göteborg, Sweden
Lunds Universitetssjukhus, Neurokirurgiska avd. NIVA
🇸🇪Lund, Sweden
Linköping Universitetssjukhuset, Neurokirurgiska kliniken
🇸🇪Linköping, Sweden
Mayo clinic, Dept of Neurosurgery
🇺🇸Jacksonville, Florida, United States
The Ohio State University - Wexner Medical Center
🇺🇸Columbus, Ohio, United States
Heinrich-Heine Universität Düsseldorf -Klinik für Neurochirugie
🇩🇪Düsseldorf, Germany
Corporació Sanitària Parc Taulí, Hospital Parc Taulí
🇪🇸Sabadell, Spain
Universitätsklinikum Schleswig Hollstein Lübeck (UKSH) Klinik für Neurochirugie
🇩🇪Lübeck, Germany
Stanford Hospital & Clinics - Stanford School of Medicine Dept. of Neurosurgery
🇺🇸Stanford, California, United States
University of Maryland Medical Systems - Neurosurgery
🇺🇸Baltimore, Maryland, United States
Virginia Commonwealth University, Department of Neurosurgery
🇺🇸Richmond, Virginia, United States
Columbia University Medical Center Dept. of Neurology - Neurological Intensive Care Unit
🇺🇸New York, New York, United States
University Hospital Sart Tilman Liege
🇧🇪Liège, Belgium
Fakultní nemocnice Ostrava Neurochirurgická klinika
🇨🇿Ostrava-Poruba, Czechia
Azienda Ospedaliero Universitaria di Parma, struttura complessa Neurochirurgia
🇮🇹Parma, Italy
Hospital Universitari son Espases
🇪🇸Palma De Mallorca, Spain