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

NCT03585270 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: ID-054-3042018-000241-39
• Study Type: interventional
• Target: 409
• Locations: 15 countries
• Sites: 80

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.

Conditions

Aneurysmal Subarachnoid Hemorrhage

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Occurrence of Clinically Relevant Cerebral Infarction at Day 16 Post-study Drug Initiation

  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)

  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

  At Week 12 post-aneurysmal subarachnoid hemorrhage (aSAH)

Other Outcomes (3)

• 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)

  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

  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

  Up to 14 days post-study drug initiation

Study Arms (2)

Clazosentan

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Clazosentan DRUG

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

Also known as: ACT-108475

Clazosentan

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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,
• 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,

Sponsors & Collaborators

• Idorsia Pharmaceuticals Ltd.: lead

Study Sites (80)

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

Stanford, California, 94305, United States

Location

Mayo clinic, Dept of Neurosurgery

Jacksonville, Florida, 32224, United States

Location

University of Illinois - Department of Neurosurgery

Chicago, Illinois, 60612, United States

Location

University of Maryland Medical Systems - Neurosurgery

Baltimore, Maryland, 21201, United States

Location

Boston University School of Medicine / Boston University Medical Center

Boston, Massachusetts, 02118, United States

Location

Beth Israel Deaconess Medical Center Dept of Neurosurgery

Boston, Massachusetts, 02215, United States

Location

Northwell Health, Department of Neurosurgery

Manhasset, New York, 11030, United States

Location

Mt Sinai Hospital

New York, New York, 10029, United States

Location

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

New York, New York, 10032, United States

Location

University Hospitals Case Medical Center - Department of Neurosurgery

Cleveland, Ohio, 44106, United States

Location

The Ohio State University - Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Oklahoma University Health Sciences Center - Department of Neurology

Oklahoma City, Oklahoma, 73104, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Penn State Milton S Hershey Medical Center, Neurosurgery

Hershey, Pennsylvania, 17033, United States

Location

Vanderbilt University Medical Center - Department of Neurosurgery

Nashville, Tennessee, 37232, United States

Location

Virginia Commonwealth University, Department of Neurosurgery

Richmond, Virginia, 23298, United States

Location

Medizinische Universität Innsbruck; Universitätsklinik für Neurologie und Psychiatrie

Innsbruck, 6020, Austria

Location

Kepler Universitätsklinikum, Universitätsklinik für Neurochirurgie

Linz, A-4020, Austria

Location

Hospital Erasme, Service de Soins Intensifs

Brussels, 1070, Belgium

Location

Hospital - Cliniques Universitaires Saint-Luc, Service de Neurochirurgie

Brussels, 1200, Belgium

Location

Neurology Department, University Hospital

Ghent, 9000, Belgium

Location

University Hospital Sart Tilman Liege

Liège, 4000, Belgium

Location

University of Alberta Hospital Department of Neurological Surgery

Edmonton, Alberta, T6G 2B7, Canada

Location

Winnipeg Regional Health Authority Health Sciences Centre

Winnipeg, Manitoba, R3A 1R9, Canada

Location

Halifax Infirmary, Nova Scotia Health Authority

Halifax, Nova Scotia, B3H 3A7, Canada

Location

Royal University Hospital Department of Neurology

Saskatoon, Saskatchewan, S7N 0W8, Canada

Location

Fakultní nemocnice Brno Neurochirurgická klinika

Brno, 625 00, Czechia

Location

Fakultní nemocnice Ostrava Neurochirurgická klinika

Ostrava-Poruba, 708 52, Czechia

Location

University Hospital in Pilsen, Department of Neurosurgery

Pilsen, 304 60, Czechia

Location

Ústřední vojenská nemocnice Praha Neurochirurgická klinika

Prague, 169 02, Czechia

Location

Masarykova nemocnice v Ústí nad Labem Neurochirurgie

Ústí nad Labem, 401 13, Czechia

Location

Odense Universitets Hospital Neurokirurgisk afdelning

Odense, 5000, Denmark

Location

Helsingin yliopistollinen keskussairaala Neurokirurgian klinikka

Helsinki, 00260, Finland

Location

Kuopio University Hospital

Kuopio, 70210, Finland

Location

Tampereen yliopistollinen sairaala Neurokirurgian klinika

Tampere, 33520, Finland

Location

Turku University Hospital Neurosurgery, T-hospital

Turku, 20520, Finland

Location

Hôpital neurologique Pierre Wertheimer Service de Reanimation

Bron, 69006, France

Location

Hôpital Gabriel Montpied, ICU DEPT, Neuro reanimation departement

Clermont-Ferrand, 63003, France

Location

Hôpital de la Timone 2, Intensive Care Unit SAR 1

Marseille, 13385, France

Location

Hôpital Nord Laennec - CHU de Nantes

Nantes, 44093, France

Location

Hospital Lariboisiere Paris

Paris, 75010, France

Location

Hôpital Pitié-Salpêtrière, Service de neuroréanimation chirurgicale Babinski

Paris, 75013, France

Location

Univ Hosp Toulouse, University Hospital Purpan Pierre Paul Riquet Hospital

Toulouse, 31059, France

Location

Klinik für Diagnostische Radiologie und Neuroradiologie, Augsburg

Augsburg, 86156, Germany

Location

Charite Universitätsmedizin Berlin - Klinik und Poliklinik für Neurochirurgie

Berlin, 10117, Germany

Location

Heinrich-Heine Universität Düsseldorf -Klinik für Neurochirugie

Düsseldorf, 40225, Germany

Location

University of Erlangen-Nürnberg, Dpt. of Neurosurgery

Erlangen, 91054, Germany

Location

University Hospital of Essen, Department of Neurosurgery

Essen, 45147, Germany

Location

Universitätsklinik Frankfurt, Klinik und Poliklinik für Neurochirurgie, Dept of neurosurgery

Frankfurt, 60528, Germany

Location

Bezirkskrankenhaus Günzburg - Klinik für Neurochirugie

Günzburg, 89132, Germany

Location

Asklepios Klinik St. Georg - Neurochirugie

Hamburg, 20099, Germany

Location

University Hospital of Hamburg-Eppendorf, Dpt. of Neurosurgery

Hamburg, 20246, Germany

Location

Neurochirurgische Universitätklinik des Heidelberg, Dept of Neurosurgery

Heidelberg, 69120, Germany

Location

Universitätsklinikum Schleswig Hollstein Lübeck (UKSH) Klinik für Neurochirugie

Lübeck, 23538, Germany

Location

University Regensburg, Dpt. of Neurosurgery

Regensburg, 93053, Germany

Location

Universitätsklinikum Rostock, Abteilung für Neurochirurgie

Rostock, 18057, Germany

Location

Debreceni Egyetem, Idegsebészet

Debrecen, 4032, Hungary

Location

Pécsi Tudományegyetem Klinikai Központ, Idegsebészeti Klinika

Pécs, 7623, Hungary

Location

Rambam Healthcare Campus, Neurology Department

Haifa, 3109601, Israel

Location

Hadassah Medical Center

Jerusalem, 9112001, Israel

Location

Beilinson Hospital, Rabin Medical Center, Department of Neurosurgery

Petah Tikva, 4941492, Israel

Location

The Chaim Sheba Medical Centre - Neurosurgery

Ramat Gan, 5265601, Israel

Location

ASST Monza, Hospital San Gerardo, TERAPIA INTENSIVA Neurochirurgica

Monza, 20900, Italy

Location

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

Padua, 35128, Italy

Location

Azienda Ospedaliero Universitaria di Parma, struttura complessa Neurochirurgia

Parma, 43126, Italy

Location

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

Rome, 00168, Italy

Location

Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego

Lodz, 90-153, Poland

Location

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

Poznan, 60-355, Poland

Location

Katedra i Klinika Neurochirurgii Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie

Warsaw, 02-097, Poland

Location

Hospital Universitario Germans Trias i Pujol - Neurology Department

Badalona, 08916, Spain

Location

Hospital Vall d'Hebron Departamento Neuroradiología

Barcelona, 08035, Spain

Location

Hospital Clinic Barcelona

Barcelona, 08036, Spain

Location

Hospital Universitari de Bellvitge

L'Hospitalet de Llobregat, 08907, Spain

Location

University Hospital of Gran Canaria Dr. Negrin

Las Palmas de Gran Canaria, 35010, Spain

Location

Hospital Universitario 12 de Octubre, Departamento Neurosurgery Division Neuroradiology

Madrid, 28041, Spain

Location

Hospital Universitari son Espases

Palma de Mallorca, 07014, Spain

Location

Corporació Sanitària Parc Taulí, Hospital Parc Taulí

Sabadell, 08208, Spain

Location

Sahlgrenska Universitetssjukhuset, Verksamheten för neurokirurgi, Neurosjukvården

Gothenburg, 41345, Sweden

Location

Linköping Universitetssjukhuset, Neurokirurgiska kliniken

Linköping, 58185, Sweden

Location

Lunds Universitetssjukhus, Neurokirurgiska avd. NIVA

Lund, 22185, Sweden

Location

Related Publications (2)

• 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.

  PMID: 39126720 DERIVED

• 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.

  PMID: 36539711 DERIVED

MeSH Terms

Conditions

Subarachnoid Hemorrhage

Interventions

clazosentan

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Idorsia Clinical Trial Information
• Organization: Idorsia Pharmaceutical Ltd

idorsiaclinicaltrials@idorsia.com

+1 856 661 3721

Study Officials

• Clinical Trials

  Idorsia Pharmaceuticals Ltd.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 29, 2018
• First Posted: July 12, 2018
• Study Start: February 3, 2019
• Primary Completion: June 13, 2022
• Study Completion: November 18, 2022
• Last Updated: January 10, 2024
• Results First Posted: January 10, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

SE (3); FR (7); ES (8); HU (2); AU (2); IL (4); DE (13); CA (4); DK (1); BE (4); US (16); CZ (5); IT (4); PL (3); FI (4)