Clinical trial NCT03585270: 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
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Aneurysmal Subarachnoid Hemorrhage
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2018-07-12
Enrollment: 409
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Occurrence of Clinical Deterioration Due to Delayed Cerebral Ischemia (DCI) From Study Drug Initiation up to 14 Days Post-study Drug Initiation
timeFrame: Up to 14 days post-study drug initiation
Secondary outcomes:
measure: Occurrence of Clinically Relevant Cerebral Infarction at Day 16 Post-study Drug Initiation
timeFrame: At Day 16 post study drug initiation
measure: Long-term Clinical Outcome Assessed by the Modified Rankin Scale (mRS) at Week 12 Post-aneurysmal Subarachnoid Hemorrhage (aSAH)
timeFrame: At Week 12 post-aneurysmal subarachnoid hemorrhage (aSAH)
measure: Long-term Clinical Outcome Assessed by the Glasgow Outcome Scale Extended (GOSE) at Week 12 Post-aSAH
timeFrame: At Week 12 post-aneurysmal subarachnoid hemorrhage (aSAH)
Other outcomes:
measure: 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)
timeFrame: Up to 14 days post-study drug initiation
measure: 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
timeFrame: Up to 14 days post-study drug initiation
measure: 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
timeFrame: Up to 14 days post-study drug initiation
Locations:
city: Stanford
country: United States
facility: Stanford Hospital & Clinics - Stanford School of Medicine Dept. of Neurosurgery
state: California
city: Jacksonville
country: United States
facility: Mayo clinic, Dept of Neurosurgery
state: Florida
city: Chicago
country: United States
facility: University of Illinois - Department of Neurosurgery
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Systems - Neurosurgery
state: Maryland
city: Boston
country: United States
facility: Boston University School of Medicine / Boston University Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center Dept of Neurosurgery
state: Massachusetts
city: Manhasset
country: United States
facility: Northwell Health, Department of Neurosurgery
state: New York
city: New York
country: United States
facility: Mt Sinai Hospital
state: New York
city: New York
country: United States
facility: Columbia University Medical Center Dept. of Neurology - Neurological Intensive Care Unit
state: New York
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center - Department of Neurosurgery
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University - Wexner Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Health Sciences Center - Department of Neurology
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center, Neurosurgery
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center - Department of Neurosurgery
state: Tennessee
city: Richmond
country: United States
facility: Virginia Commonwealth University, Department of Neurosurgery
state: Virginia
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck; Universitätsklinik für Neurologie und Psychiatrie
city: Linz
country: Austria
facility: Kepler Universitätsklinikum, Universitätsklinik für Neurochirurgie
city: Brussels
country: Belgium
facility: Hospital Erasme, Service de Soins Intensifs
city: Brussels
country: Belgium
facility: Hospital - Cliniques Universitaires Saint-Luc, Service de Neurochirurgie
city: Gent
country: Belgium
facility: Neurology Department, University Hospital
city: Liège
country: Belgium
facility: University Hospital Sart Tilman Liege
city: Edmonton
country: Canada
facility: University of Alberta Hospital Department of Neurological Surgery
state: Alberta
city: Winnipeg
country: Canada
facility: Winnipeg Regional Health Authority Health Sciences Centre
state: Manitoba
city: Halifax
country: Canada
facility: Halifax Infirmary, Nova Scotia Health Authority
state: Nova Scotia
city: Saskatoon
country: Canada
facility: Royal University Hospital Department of Neurology
state: Saskatchewan
city: Brno
country: Czechia
facility: Fakultní nemocnice Brno Neurochirurgická klinika
city: Ostrava-Poruba
country: Czechia
facility: Fakultní nemocnice Ostrava Neurochirurgická klinika
city: Plzen
country: Czechia
facility: University Hospital in Pilsen, Department of Neurosurgery
city: Praha
country: Czechia
facility: Ústřední vojenská nemocnice Praha Neurochirurgická klinika
city: Ústí Nad Labem
country: Czechia
facility: Masarykova nemocnice v Ústí nad Labem Neurochirurgie
city: Odense
country: Denmark
facility: Odense Universitets Hospital Neurokirurgisk afdelning
city: Helsinki
country: Finland
facility: Helsingin yliopistollinen keskussairaala Neurokirurgian klinikka
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala Neurokirurgian klinika
city: Turku
country: Finland
facility: Turku University Hospital Neurosurgery, T-hospital
city: Bron
country: France
facility: Hôpital neurologique Pierre Wertheimer Service de Reanimation
city: Clermont-Ferrand
country: France
facility: Hôpital Gabriel Montpied, ICU DEPT, Neuro reanimation departement
city: Marseille
country: France
facility: Hôpital de la Timone 2, Intensive Care Unit SAR 1
city: Nantes
country: France
facility: Hôpital Nord Laennec - CHU de Nantes
city: Paris
country: France
facility: Hospital Lariboisiere Paris
city: Paris
country: France
facility: Hôpital Pitié-Salpêtrière, Service de neuroréanimation chirurgicale Babinski
city: Toulouse
country: France
facility: Univ Hosp Toulouse, University Hospital Purpan Pierre Paul Riquet Hospital
city: Augsburg
country: Germany
facility: Klinik für Diagnostische Radiologie und Neuroradiologie, Augsburg
city: Berlin
country: Germany
facility: Charite Universitätsmedizin Berlin - Klinik und Poliklinik für Neurochirurgie
city: Düsseldorf
country: Germany
facility: Heinrich-Heine Universität Düsseldorf -Klinik für Neurochirugie
city: Erlangen
country: Germany
facility: University of Erlangen-Nürnberg, Dpt. of Neurosurgery
city: Essen
country: Germany
facility: University Hospital of Essen, Department of Neurosurgery
city: Frankfurt
country: Germany
facility: Universitätsklinik Frankfurt, Klinik und Poliklinik für Neurochirurgie, Dept of neurosurgery
city: Günzburg
country: Germany
facility: Bezirkskrankenhaus Günzburg - Klinik für Neurochirugie
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg - Neurochirugie
city: Hamburg
country: Germany
facility: University Hospital of Hamburg-Eppendorf, Dpt. of Neurosurgery
city: Heidelberg
country: Germany
facility: Neurochirurgische Universitätklinik des Heidelberg, Dept of Neurosurgery
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig Hollstein Lübeck (UKSH) Klinik für Neurochirugie
city: Regensburg
country: Germany
facility: University Regensburg, Dpt. of Neurosurgery
city: Rostock
country: Germany
facility: Universitätsklinikum Rostock, Abteilung für Neurochirurgie
city: Debrecen
country: Hungary
facility: Debreceni Egyetem, Idegsebészet
city: Pécs
country: Hungary
facility: Pécsi Tudományegyetem Klinikai Központ, Idegsebészeti Klinika
city: Haifa
country: Israel
facility: Rambam Healthcare Campus, Neurology Department
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Petah tikva
country: Israel
facility: Beilinson Hospital, Rabin Medical Center, Department of Neurosurgery
city: Ramat Gan
country: Israel
facility: The Chaim Sheba Medical Centre - Neurosurgery
city: Monza
country: Italy
facility: ASST Monza, Hospital San Gerardo, TERAPIA INTENSIVA Neurochirurgica
city: Padova
country: Italy
facility: Azienda Ospedaliera Padova-Università degli Studi di Padova - Istituto di Anestesia e Rianimazione
city: Parma
country: Italy
facility: Azienda Ospedaliero Universitaria di Parma, struttura complessa Neurochirurgia
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli Università Cattolica del Sacro Cuore, UOS Terapia Intensiva Neurochirurgic
city: Poznań
country: Poland
facility: Oddział Neurochirurgii i Neurotraumatologii z Pododdziałem Leczenia Chorób Naczyniowych Centralnego Układu Nerwowego
city: Warszawa
country: Poland
facility: Katedra i Klinika Neurochirurgii Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie
city: Łódź
country: Poland
facility: Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol - Neurology Department
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron Departamento Neuroradiología
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge
city: Las Palmas De Gran Canaria
country: Spain
facility: University Hospital of Gran Canaria Dr. Negrin
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre, Departamento Neurosurgery Division Neuroradiology
city: Palma De Mallorca
country: Spain
facility: Hospital Universitari son Espases
city: Sabadell
country: Spain
facility: Corporació Sanitària Parc Taulí, Hospital Parc Taulí
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset, Verksamheten för neurokirurgi, Neurosjukvården
city: Linköping
country: Sweden
facility: Linköping Universitetssjukhuset, Neurokirurgiska kliniken
city: Lund
country: Sweden
facility: Lunds Universitetssjukhus, Neurokirurgiska avd. NIVA
Study officials:
affiliation: Idorsia Pharmaceuticals Ltd.
name: Clinical Trials
role: STUDY_DIRECTOR
References: