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

NCT ID: NCT03585270

Last Updated: 2024-01-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 409 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-03
• Study Completion Date: 2022-11-18

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.

Conditions

Aneurysmal Subarachnoid Hemorrhage

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

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).

Group Type: EXPERIMENTAL

Clazosentan

Intervention Type: DRUG

Clazosentan will be administered as a continuous intravenous infusion at the dose of 15 mg/hour for up to 14 days.

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).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo will be administered at the same infusion rate as clazosentan for up to 14 days.

Interventions

Clazosentan

Clazosentan will be administered as a continuous intravenous infusion at the dose of 15 mg/hour for up to 14 days.

Intervention Type: DRUG

Placebo

Placebo will be administered at the same infusion rate as clazosentan for up to 14 days.

Intervention Type: DRUG

Other Intervention Names

ACT-108475

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Idorsia Pharmaceuticals Ltd.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Idorsia Pharmaceuticals Ltd.

Locations

Stanford Hospital & Clinics - Stanford School of Medicine Dept. of Neurosurgery

Stanford, California, United States

Mayo clinic, Dept of Neurosurgery

Jacksonville, Florida, United States

University of Illinois - Department of Neurosurgery

Chicago, Illinois, United States

University of Maryland Medical Systems - Neurosurgery

Baltimore, Maryland, United States

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

Northwell Health, Department of Neurosurgery

Manhasset, New York, United States

Mt Sinai Hospital

New York, New York, United States

Columbia University Medical Center Dept. of Neurology - Neurological Intensive Care Unit

New York, New York, United States

University Hospitals Case Medical Center - Department of Neurosurgery

Cleveland, Ohio, United States

The Ohio State University - Wexner Medical Center

Columbus, Ohio, 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

Vanderbilt University Medical Center - Department of Neurosurgery

Nashville, Tennessee, United States

Virginia Commonwealth University, Department of Neurosurgery

Richmond, Virginia, United States

Medizinische Universität Innsbruck; Universitätsklinik für Neurologie und Psychiatrie

Innsbruck, , Austria

Kepler Universitätsklinikum, Universitätsklinik für Neurochirurgie

Linz, , Austria

Hospital Erasme, Service de Soins Intensifs

Brussels, , Belgium

Hospital - Cliniques Universitaires Saint-Luc, Service de Neurochirurgie

Brussels, , Belgium

Neurology Department, University Hospital

Ghent, , Belgium

University Hospital Sart Tilman Liege

Liège, , Belgium

University of Alberta Hospital Department of Neurological Surgery

Edmonton, Alberta, Canada

Winnipeg Regional Health Authority Health Sciences Centre

Winnipeg, Manitoba, Canada

Halifax Infirmary, Nova Scotia Health Authority

Halifax, Nova Scotia, Canada

Royal University Hospital Department of Neurology

Saskatoon, Saskatchewan, Canada

Fakultní nemocnice Brno Neurochirurgická klinika

Brno, , Czechia

Fakultní nemocnice Ostrava Neurochirurgická klinika

Ostrava-Poruba, , Czechia

University Hospital in Pilsen, Department of Neurosurgery

Pilsen, , Czechia

Ústřední vojenská nemocnice Praha Neurochirurgická klinika

Prague, , Czechia

Masarykova nemocnice v Ústí nad Labem Neurochirurgie

Ústí nad Labem, , Czechia

Odense Universitets Hospital Neurokirurgisk afdelning

Odense, , Denmark

Helsingin yliopistollinen keskussairaala Neurokirurgian klinikka

Helsinki, , Finland

Kuopio University Hospital

Kuopio, , Finland

Tampereen yliopistollinen sairaala Neurokirurgian klinika

Tampere, , Finland

Turku University Hospital Neurosurgery, T-hospital

Turku, , Finland

Hôpital neurologique Pierre Wertheimer Service de Reanimation

Bron, , France

Hôpital Gabriel Montpied, ICU DEPT, Neuro reanimation departement

Clermont-Ferrand, , France

Hôpital de la Timone 2, Intensive Care Unit SAR 1

Marseille, , France

Hôpital Nord Laennec - CHU de Nantes

Nantes, , France

Hospital Lariboisiere Paris

Paris, , France

Hôpital Pitié-Salpêtrière, Service de neuroréanimation chirurgicale Babinski

Paris, , France

Univ Hosp Toulouse, University Hospital Purpan Pierre Paul Riquet Hospital

Toulouse, , France

Klinik für Diagnostische Radiologie und Neuroradiologie, Augsburg

Augsburg, , Germany

Charite Universitätsmedizin Berlin - Klinik und Poliklinik für Neurochirurgie

Berlin, , Germany

Heinrich-Heine Universität Düsseldorf -Klinik für Neurochirugie

Düsseldorf, , Germany

University of Erlangen-Nürnberg, Dpt. of Neurosurgery

Erlangen, , 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

Neurochirurgische Universitätklinik des Heidelberg, Dept of Neurosurgery

Heidelberg, , Germany

Universitätsklinikum Schleswig Hollstein Lübeck (UKSH) Klinik für Neurochirugie

Lübeck, , Germany

University Regensburg, Dpt. of Neurosurgery

Regensburg, , Germany

Universitätsklinikum Rostock, Abteilung für Neurochirurgie

Rostock, , Germany

Debreceni Egyetem, Idegsebészet

Debrecen, , Hungary

Pécsi Tudományegyetem Klinikai Központ, Idegsebészeti Klinika

Pécs, , Hungary

Rambam Healthcare Campus, Neurology Department

Haifa, , Israel

Hadassah Medical Center

Jerusalem, , Israel

Beilinson Hospital, Rabin Medical Center, Department of Neurosurgery

Petah Tikva, , Israel

The Chaim Sheba Medical Centre - Neurosurgery

Ramat Gan, , Israel

ASST Monza, Hospital San Gerardo, TERAPIA INTENSIVA Neurochirurgica

Monza, , Italy

Azienda Ospedaliera Padova-Università degli Studi di Padova - Istituto di Anestesia e Rianimazione

Padua, , Italy

Azienda Ospedaliero Universitaria di Parma, struttura complessa Neurochirurgia

Parma, , Italy

Fondazione Policlinico Universitario Agostino Gemelli Università Cattolica del Sacro Cuore, UOS Terapia Intensiva Neurochirurgic

Rome, , Italy

Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego

Lodz, , Poland

Oddział Neurochirurgii i Neurotraumatologii z Pododdziałem Leczenia Chorób Naczyniowych Centralnego Układu Nerwowego

Poznan, , Poland

Katedra i Klinika Neurochirurgii Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie

Warsaw, , Poland

Hospital Universitario Germans Trias i Pujol - Neurology Department

Badalona, , Spain

Hospital Vall d'Hebron Departamento Neuroradiología

Barcelona, , Spain

Hospital Clinic Barcelona

Barcelona, , Spain

Hospital Universitari de Bellvitge

L'Hospitalet de Llobregat, , Spain

University Hospital of Gran Canaria Dr. Negrin

Las Palmas de Gran Canaria, , Spain

Hospital Universitario 12 de Octubre, Departamento Neurosurgery Division Neuroradiology

Madrid, , Spain

Hospital Universitari son Espases

Palma de Mallorca, , Spain

Corporació Sanitària Parc Taulí, Hospital Parc Taulí

Sabadell, , Spain

Sahlgrenska Universitetssjukhuset, Verksamheten för neurokirurgi, Neurosjukvården

Gothenburg, , Sweden

Linköping Universitetssjukhuset, Neurokirurgiska kliniken

Linköping, , Sweden

Lunds Universitetssjukhus, Neurokirurgiska avd. NIVA

Lund, , Sweden

Countries

United States; Austria; Belgium; Canada; Czechia; Denmark; Finland; France; Germany; Hungary; Israel; Italy; Poland; Spain; Sweden

References

Mayer SA, Bruder N, Citerio G, Defreyne L, Dubois C, Gupta R, Higashida R, Marr A, Nguyen TN, Roux S, Smrcka M, Torne RT, Aldrich EF; on behalf of the REACT investigators. REACT: a randomized trial to assess the efficacy and safety of clazosentan for preventing clinical deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2024 Aug 9;142(1):98-109. doi: 10.3171/2024.4.JNS232191. Print 2025 Jan 1.

Reference Type: DERIVED

PMID: 39126720 (View on PubMed)

Bruder N, Higashida R, Santin-Janin H, Dubois C, Aldrich EF, Marr A, Roux S, Mayer SA. The REACT study: design of a randomized phase 3 trial to assess the efficacy and safety of clazosentan for preventing deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. BMC Neurol. 2022 Dec 20;22(1):492. doi: 10.1186/s12883-022-03002-8.

Reference Type: DERIVED

PMID: 36539711 (View on PubMed)

Provided Documents

Document Type: Study Protocol: Protocol

View Document

Document Type: Study Protocol: Addendum to protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018-000241-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ID-054-304

Identifier Type: -

Identifier Source: org_study_id