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

Aneurysmal Subarachnoid Hemorrhage Clinical Trial

— REACT  

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03585270
• Other study ID #: ID-054-304
• Secondary ID: 2018-000241-39
• Status: Completed
• Phase: Phase 3
• Start date: February 3, 2019
• Est. completion date: November 18, 2022

Study information

• Verified date: December 2023
• Source: Idorsia Pharmaceuticals Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 409
• Est. completion date: November 18, 2022
• Est. primary completion date: June 13, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Aneurysmal Subarachnoid Hemorrhage
• Hemorrhage
• Subarachnoid Hemorrhage

Intervention

Drug:
• Clazosentan
Clazosentan will be administered as a continuous intravenous infusion at the dose of 15 mg/hour for up to 14 days.
• Placebo
Placebo will be administered at the same infusion rate as clazosentan for up to 14 days.

Locations

Country	Name	City	State
Austria	Medizinische Universität Innsbruck; Universitätsklinik für Neurologie und Psychiatrie	Innsbruck
Austria	Kepler Universitätsklinikum, Universitätsklinik für Neurochirurgie	Linz
Belgium	Hospital - Cliniques Universitaires Saint-Luc, Service de Neurochirurgie	Brussels
Belgium	Hospital Erasme, Service de Soins Intensifs	Brussels
Belgium	Neurology Department, University Hospital	Gent
Belgium	University Hospital Sart Tilman Liege	Liège
Canada	University of Alberta Hospital Department of Neurological Surgery	Edmonton	Alberta
Canada	Halifax Infirmary, Nova Scotia Health Authority	Halifax	Nova Scotia
Canada	Royal University Hospital Department of Neurology	Saskatoon	Saskatchewan
Canada	Winnipeg Regional Health Authority Health Sciences Centre	Winnipeg	Manitoba
Czechia	Fakultní nemocnice Brno Neurochirurgická klinika	Brno
Czechia	Fakultní nemocnice Ostrava Neurochirurgická klinika	Ostrava-Poruba
Czechia	University Hospital in Pilsen, Department of Neurosurgery	Plzen
Czechia	Ústrední vojenská nemocnice Praha Neurochirurgická klinika	Praha
Czechia	Masarykova nemocnice v Ústí nad Labem Neurochirurgie	Ústí Nad Labem
Denmark	Odense Universitets Hospital Neurokirurgisk afdelning	Odense
Finland	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
France	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	Hôpital Pitié-Salpêtrière, Service de neuroréanimation chirurgicale Babinski	Paris
France	Hospital Lariboisiere Paris	Paris
France	Univ Hosp Toulouse, University Hospital Purpan Pierre Paul Riquet Hospital	Toulouse
Germany	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
Hungary	Debreceni Egyetem, Idegsebészet	Debrecen
Hungary	Pécsi Tudományegyetem Klinikai Központ, Idegsebészeti Klinika	Pécs
Israel	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
Italy	ASST Monza, Hospital San Gerardo, TERAPIA INTENSIVA Neurochirurgica	Monza
Italy	Azienda Ospedaliera Padova-Università degli Studi di Padova - Istituto di Anestesia e Rianimazione	Padova
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
Poland	Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego	Lódz
Poland	Oddzial Neurochirurgii i Neurotraumatologii z Pododdzialem Leczenia Chorób Naczyniowych Centralnego Ukladu Nerwowego	Poznan
Poland	Katedra i Klinika Neurochirurgii Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie	Warszawa
Spain	Hospital Universitario Germans Trias i Pujol - Neurology Department	Badalona
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Hospital Vall d'Hebron Departamento Neuroradiología	Barcelona
Spain	Hospital Universitari de Bellvitge	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
Sweden	Sahlgrenska Universitetssjukhuset, Verksamheten för neurokirurgi, Neurosjukvården	Göteborg
Sweden	Linköping Universitetssjukhuset, Neurokirurgiska kliniken	Linköping
Sweden	Lunds Universitetssjukhus, Neurokirurgiska avd. NIVA	Lund
United States	University of Maryland Medical Systems - Neurosurgery	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center Dept of Neurosurgery	Boston	Massachusetts
United States	Boston University School of Medicine / Boston University Medical Center	Boston	Massachusetts
United States	University of Illinois - Department of Neurosurgery	Chicago	Illinois
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	Penn State Milton S Hershey Medical Center, Neurosurgery	Hershey	Pennsylvania
United States	Mayo clinic, Dept of Neurosurgery	Jacksonville	Florida
United States	Northwell Health, Department of Neurosurgery	Manhasset	New York
United States	Vanderbilt University Medical Center - Department of Neurosurgery	Nashville	Tennessee
United States	Columbia University Medical Center Dept. of Neurology - Neurological Intensive Care Unit	New York	New York
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	Virginia Commonwealth University, Department of Neurosurgery	Richmond	Virginia
United States	Stanford Hospital & Clinics - Stanford School of Medicine Dept. of Neurosurgery	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Idorsia Pharmaceuticals Ltd.

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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)
Secondary	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)