Evaluation of the Efficacy and Safety of Clazosentan in Reversing Cerebral Vasospasm in Adult Subjects With Aneurysmal Subarachnoid Hemorrhage (REVERSE)

A Prospective, Multi-center, Open-label, Single-arm, Phase 2 Study to Assess the Efficacy and Safety of Clazosentan in Reversing Angiographically-confirmed Cerebral Vasospasm in Adult Subjects With Aneurysmal Subarachnoid Hemorrhage (aSAH) Treated by Surgical Clipping or Endovascular Coiling

The purpose of this study is to evaluate the safety and potential therapeutic benefit of use of clazosentan in reversing cerebral vasospasm (a narrowing of blood vessels in the brain due to the presence of blood in the space around the brain) in patients who have suffered a condition known as aneurysmal subarachnoid hemorrhage caused by bleeding onto the surface of the brain from a ruptured brain aneurysm

Study Overview

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

Detailed Description

Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by bleeding onto the brain surface due to a rupture of a pouch or bulge in a brain vessel (called an aneurysm). It is a rare but serious condition with a high risk of death. Even patients who have had successful repair of the aneurysm remain at risk for developing cerebral vasospasm, which can result in harmful conditions related to the lack of oxygen to parts of the brain and death. Cerebral vasospasm usually occurs within the first couple of weeks after aSAH, and it is difficult to treat. Currently there is no safe, efficacious and widely available treatment. Previous animal studies have shown that a new drug under investigation, clazosentan, was able to reverse cerebral vasospasm in animal models of SAH. A first trial conducted in a small number of patients showed some benefit of clazosentan in reversing established cerebral vasospasm after aSAH. Clazosentan has already been evaluated in the prevention of cerebral vasospasm in several large clinical trials in aSAH. This current study aims to evaluate if clazosentan is effective and safe in the treatment of cerebral vasospasm after aSAH.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, 00260
    • Site 2002
• France
  • Bron, France, 69677
    • Site 1002
  • Clermont Ferrand, France, 63003
    • Site 1006
  • Marseille, France, 13385
    • Site 1004
  • Montpellier, France, 34295
    • Site 1005
  • Paris, France, 75013
    • Site 1001
• Switzerland
  • Aarau, Switzerland, 5001
    • Site 3005
  • Basel, Switzerland, 4031
    • Site 3001
  • Bern, Switzerland, 3010
    • Site 3003
  • Geneva, Switzerland, 1211
    • Site 3004
  • Zürich, Switzerland, 8091
    • Site 3002

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent from the subject or proxy/legal representative
• Aneurysmal subarachnoid hemorrhage (aSAH)confirmed by digital subtraction angiogram (DSA) or computed tomography angiogram (CTA), successfully secured by surgical clipping or endovascular coiling within 72 hours of rupture
• World Federation of Neurological Surgeons (WFNS) grade 1-4 at admission, and which must not increase to grade 5 at the time of enrollment
• Moderate or severe global cerebral vasospasm at the time of enrollment, documented by digital subtraction angiography (DSA) performed not earlier than 48 hours post aneurysm-securing procedure
• Women of childbearing potential must have a negative serum pregnancy test at screening and must use a reliable method of contraception from hospital discharge up to 30 days after discontinuation of study drug infusion, and fertile males must use a condom as a contraceptive method during this same period

Exclusion Criteria:

• SAH due to causes other than a saccular aneurysm
• Any moderate or severe cerebral vasospasm on angiography prior to the aneurysm-securing procedure
• Presence of a new or worsened cerebral infarct or evidence of significant bleeding post aneurysm-securing procedure, or re-bleeding, on a CT scan performed within 24 hours prior to enrollment
• 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
• Any severe or unstable concomitant condition or disease (e.g., cancer, hematological, or coronary disease) or chronic condition (e.g., drug abuse, severe alcoholism), which, in the opinion of the investigator, would interfere with the assessment of the safety or effect of the study treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clazosentan; Diluted solution administered as a continuous intravenous infusion at a rate of 15 mg/h for up to a cumulative maximum of 10 days	Drug: Clazosentan; Concentrated solution for intravenous injection; Other Names: ACT-108475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Successful reversal of global cerebral vasospasm 3 hours post-study drug initiation	Successful reversal is defined as an improvement in at least one level of severity on the "global vasospasm assessment" (i.e., from severe to moderate, mild, or none, or from moderate to mild or none), evaluated on Digital subtraction angiogram (DSA)	3 hours post-study drug initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Successful reversal of global cerebral vasospasm 24 hours post-study drug initiation		24 hours post-study drug initiation
Maximum change from baseline in angiographic cerebral circulation time (CCT)	CCT will be determined in the left and right anterior circulation, and the posterior circulation, on the digital subtraction angiogram (DSA) at each scheduled time point.	At baseline, 3 hours and 24 hours post-study drug initiation
Number of subjects with adverse events	An adverse event is defined as any unfavorable and unintended sign, including an abnormal laboratory finding, symptom or disease, that occurs during the course of the study, whether or not considered related to the study drug	Up to 30 days after study drug discontinuation

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.
• Investigators: Study Director: Angelina Marr, BSc. Pharm, Actelion

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Actual): May 2, 2017
• Study Completion (Actual): May 2, 2017

Study Registration Dates

• First Submitted: September 23, 2015
• First Submitted That Met QC Criteria: September 24, 2015
• First Posted (Estimate): September 25, 2015

Study Record Updates

• Last Update Posted (Actual): July 10, 2018
• Last Update Submitted That Met QC Criteria: July 6, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: cerebral vasospasm; aneurysmal subarachnoid hemorrhage; clazosentan
• 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; Vasospasm, Intracranial
• Other Study ID Numbers: AC-054-203; 2015-002721-18 (EudraCT Number)