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 (REACT)

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)

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.

Study Overview

• Status: Completed
• Conditions: Aneurysmal Subarachnoid Hemorrhage
• Intervention / Treatment: Drug: Clazosentan; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 409
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Medizinische Universität Innsbruck; Universitätsklinik für Neurologie und Psychiatrie
  • Linz, Austria, A-4020
    • Kepler Universitätsklinikum, Universitätsklinik für Neurochirurgie
• Belgium
  • Brussels, Belgium, 1070
    • Hospital Erasme, Service de Soins Intensifs
  • Brussels, Belgium, 1200
    • Hospital - Cliniques Universitaires Saint-Luc, Service de Neurochirurgie
  • Gent, Belgium, 9000
    • Neurology Department, University Hospital
  • Liège, Belgium, 4000
    • University Hospital Sart Tilman Liege
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital Department of Neurological Surgery
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Winnipeg Regional Health Authority Health Sciences Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Halifax Infirmary, Nova Scotia Health Authority
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Royal University Hospital Department of Neurology
• Czechia
  • Brno, Czechia, 625 00
    • Fakultní nemocnice Brno Neurochirurgická klinika
  • Ostrava-Poruba, Czechia, 708 52
    • Fakultní nemocnice Ostrava Neurochirurgická klinika
  • Plzen, Czechia, 304 60
    • University Hospital in Pilsen, Department of Neurosurgery
  • Praha, Czechia, 169 02
    • Ústřední vojenská nemocnice Praha Neurochirurgická klinika
  • Ústí Nad Labem, Czechia, 401 13
    • Masarykova nemocnice v Ústí nad Labem Neurochirurgie
• Denmark
  • Odense, Denmark, 5000
    • Odense Universitets Hospital Neurokirurgisk afdelning
• Finland
  • Helsinki, Finland, 00260
    • Helsingin yliopistollinen keskussairaala Neurokirurgian klinikka
  • Kuopio, Finland, 70210
    • Kuopio University Hospital
  • Tampere, Finland, 33520
    • Tampereen yliopistollinen sairaala Neurokirurgian klinika
  • Turku, Finland, 20520
    • Turku University Hospital Neurosurgery, T-hospital
• France
  • Bron, France, 69006
    • Hôpital neurologique Pierre Wertheimer Service de Reanimation
  • Clermont-Ferrand, France, 63003
    • Hôpital Gabriel Montpied, ICU DEPT, Neuro reanimation departement
  • Marseille, France, 13385
    • Hôpital de la Timone 2, Intensive Care Unit SAR 1
  • Nantes, France, 44093
    • Hôpital Nord Laennec - CHU de Nantes
  • Paris, France, 75010
    • Hospital Lariboisiere Paris
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière, Service de neuroréanimation chirurgicale Babinski
  • Toulouse, France, 31059
    • Univ Hosp Toulouse, University Hospital Purpan Pierre Paul Riquet Hospital
• Germany
  • Augsburg, Germany, 86156
    • Klinik für Diagnostische Radiologie und Neuroradiologie, Augsburg
  • Berlin, Germany, 10117
    • Charite Universitätsmedizin Berlin - Klinik und Poliklinik für Neurochirurgie
  • Düsseldorf, Germany, 40225
    • Heinrich-Heine Universität Düsseldorf -Klinik für Neurochirugie
  • Erlangen, Germany, 91054
    • University of Erlangen-Nürnberg, Dpt. of Neurosurgery
  • Essen, Germany, 45147
    • University Hospital of Essen, Department of Neurosurgery
  • Frankfurt, Germany, 60528
    • Universitätsklinik Frankfurt, Klinik und Poliklinik für Neurochirurgie, Dept of neurosurgery
  • Günzburg, Germany, 89132
    • Bezirkskrankenhaus Günzburg - Klinik für Neurochirugie
  • Hamburg, Germany, 20099
    • Asklepios Klinik St. Georg - Neurochirugie
  • Hamburg, Germany, 20246
    • University Hospital of Hamburg-Eppendorf, Dpt. of Neurosurgery
  • Heidelberg, Germany, 69120
    • Neurochirurgische Universitätklinik des Heidelberg, Dept of Neurosurgery
  • Lübeck, Germany, 23538
    • Universitätsklinikum Schleswig Hollstein Lübeck (UKSH) Klinik für Neurochirugie
  • Regensburg, Germany, 93053
    • University Regensburg, Dpt. of Neurosurgery
  • Rostock, Germany, 18057
    • Universitätsklinikum Rostock, Abteilung für Neurochirurgie
• Hungary
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem, Idegsebészet
  • Pécs, Hungary, 7623
    • Pécsi Tudományegyetem Klinikai Központ, Idegsebészeti Klinika
• Israel
  • Haifa, Israel, 3109601
    • Rambam Healthcare Campus, Neurology Department
  • Jerusalem, Israel, 9112001
    • Hadassah Medical Center
  • Petah tikva, Israel, 4941492
    • Beilinson Hospital, Rabin Medical Center, Department of Neurosurgery
  • Ramat Gan, Israel, 5265601
    • The Chaim Sheba Medical Centre - Neurosurgery
• Italy
  • Monza, Italy, 20900
    • ASST Monza, Hospital San Gerardo, TERAPIA INTENSIVA Neurochirurgica
  • Padova, Italy, 35128
    • Azienda Ospedaliera Padova-Università degli Studi di Padova - Istituto di Anestesia e Rianimazione
  • Parma, Italy, 43126
    • Azienda Ospedaliero Universitaria di Parma, struttura complessa Neurochirurgia
  • Rome, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli Università Cattolica del Sacro Cuore, UOS Terapia Intensiva Neurochirurgic
• Poland
  • Poznań, Poland, 60-355
    • Oddział Neurochirurgii i Neurotraumatologii z Pododdziałem Leczenia Chorób Naczyniowych Centralnego Układu Nerwowego
  • Warszawa, Poland, 02-097
    • Katedra i Klinika Neurochirurgii Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie
  • Łódź, Poland, 90-153
    • Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego
• Spain
  • Badalona, Spain, 08916
    • Hospital Universitario Germans Trias i Pujol - Neurology Department
  • Barcelona, Spain, 08036
    • Hospital Clinic Barcelona
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron Departamento Neuroradiología
  • Hospitalet de Llobregat, Spain, 08907
    • Hospital Universitari de Bellvitge
  • Las Palmas De Gran Canaria, Spain, 35010
    • University Hospital of Gran Canaria Dr. Negrin
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre, Departamento Neurosurgery Division Neuroradiology
  • Palma De Mallorca, Spain, 07014
    • Hospital Universitari Son Espases
  • Sabadell, Spain, 08208
    • Corporació Sanitària Parc Taulí, Hospital Parc Taulí
• Sweden
  • Göteborg, Sweden, 41345
    • Sahlgrenska Universitetssjukhuset, Verksamheten för neurokirurgi, Neurosjukvården
  • Linköping, Sweden, 58185
    • Linköping Universitetssjukhuset, Neurokirurgiska kliniken
  • Lund, Sweden, 22185
    • Lunds Universitetssjukhus, Neurokirurgiska avd. NIVA
• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Hospital & Clinics - Stanford School of Medicine Dept. of Neurosurgery
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo clinic, Dept of Neurosurgery
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois - Department of Neurosurgery
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Systems - Neurosurgery
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine / Boston University Medical Center
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center Dept of Neurosurgery
  • New York
    • Manhasset, New York, United States, 11030
      • Northwell Health, Department of Neurosurgery
    • New York, New York, United States, 10029
      • Mt Sinai Hospital
    • New York, New York, United States, 10032
      • Columbia University Medical Center Dept. of Neurology - Neurological Intensive Care Unit
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center - Department of Neurosurgery
    • Columbus, Ohio, United States, 43210
      • The Ohio State University - Wexner Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Health Sciences Center - Department of Neurology
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S Hershey Medical Center, Neurosurgery
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center - Department of Neurosurgery
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University, Department of Neurosurgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: Clazosentan; Clazosentan will be administered as a continuous intravenous infusion at the dose of 15 mg/hour for up to 14 days.; Other Names: ACT-108475
Placebo Comparator: 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).	Drug: Placebo; Placebo will be administered at the same infusion rate as clazosentan for up to 14 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From 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.	Up to 14 days post-study drug initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Clinically Relevant Cerebral Infarction 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.	At Day 16 post study drug initiation
Long-term Clinical Outcome Assessed by the Modified Rankin Scale (mRS) 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).	At Week 12 post-aneurysmal subarachnoid hemorrhage (aSAH)
Long-term Clinical Outcome Assessed by the Glasgow Outcome Scale Extended (GOSE) at Week 12 Post-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)	At Week 12 post-aneurysmal subarachnoid hemorrhage (aSAH)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation (Safety Analysis Set)	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 (CT) scans.	Up to 14 days post-study drug initiation
Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation Including Rescue Therapy for Non-relevant Vasospasm	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 Tomograph (CT) scans.	Up to 14 days post-study drug initiation
Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation Based on Neurological Scales and Death	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 Tomograph (CT) scans.	Up to 14 days post-study drug initiation

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.
• Investigators: Study Director: Clinical Trials, Idorsia Pharmaceuticals Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2019
• Primary Completion (Actual): June 13, 2022
• Study Completion (Actual): November 18, 2022

Study Registration Dates

• First Submitted: June 29, 2018
• First Submitted That Met QC Criteria: June 29, 2018
• First Posted (Actual): July 12, 2018

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: December 18, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage
• Other Study ID Numbers: ID-054-304; 2018-000241-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No