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

Primary Purpose

Aneurysmal Subarachnoid Hemorrhage

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Clazosentan
Sponsored by
Idorsia Pharmaceuticals Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aneurysmal Subarachnoid Hemorrhage focused on measuring aneurysmal subarachnoid hemorrhage, cerebral vasospasm, clazosentan

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Site 2002
  • Site 1002
  • Site 1006
  • Site 1004
  • Site 1005
  • Site 1001
  • Site 3005
  • Site 3001
  • Site 3003
  • Site 3004
  • Site 3002

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Clazosentan

Arm Description

Diluted solution administered as a continuous intravenous infusion at a rate of 15 mg/h for up to a cumulative maximum of 10 days

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Successful reversal of global cerebral vasospasm 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.
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

Full Information

First Posted
September 23, 2015
Last Updated
July 6, 2018
Sponsor
Idorsia Pharmaceuticals Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT02560532
Brief Title
Evaluation of the Efficacy and Safety of Clazosentan in Reversing Cerebral Vasospasm in Adult Subjects With Aneurysmal Subarachnoid Hemorrhage
Acronym
REVERSE
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
March 1, 2016 (undefined)
Primary Completion Date
May 2, 2017 (Actual)
Study Completion Date
May 2, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Idorsia Pharmaceuticals Ltd.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aneurysmal Subarachnoid Hemorrhage
Keywords
aneurysmal subarachnoid hemorrhage, cerebral vasospasm, clazosentan

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Clazosentan
Arm Type
Experimental
Arm Description
Diluted solution administered as a continuous intravenous infusion at a rate of 15 mg/h for up to a cumulative maximum of 10 days
Intervention Type
Drug
Intervention Name(s)
Clazosentan
Other Intervention Name(s)
ACT-108475
Intervention Description
Concentrated solution for intravenous injection
Primary Outcome Measure Information:
Title
Successful reversal of global cerebral vasospasm 3 hours post-study drug initiation
Description
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)
Time Frame
3 hours post-study drug initiation
Secondary Outcome Measure Information:
Title
Successful reversal of global cerebral vasospasm 24 hours post-study drug initiation
Time Frame
24 hours post-study drug initiation
Title
Maximum change from baseline in angiographic cerebral circulation time (CCT)
Description
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.
Time Frame
At baseline, 3 hours and 24 hours post-study drug initiation
Title
Number of subjects with adverse events
Description
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
Time Frame
Up to 30 days after study drug discontinuation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Angelina Marr, BSc. Pharm
Organizational Affiliation
Actelion
Official's Role
Study Director
Facility Information:
Facility Name
Site 2002
City
Helsinki
ZIP/Postal Code
00260
Country
Finland
Facility Name
Site 1002
City
Bron
ZIP/Postal Code
69677
Country
France
Facility Name
Site 1006
City
Clermont Ferrand
ZIP/Postal Code
63003
Country
France
Facility Name
Site 1004
City
Marseille
ZIP/Postal Code
13385
Country
France
Facility Name
Site 1005
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Name
Site 1001
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Name
Site 3005
City
Aarau
ZIP/Postal Code
5001
Country
Switzerland
Facility Name
Site 3001
City
Basel
ZIP/Postal Code
4031
Country
Switzerland
Facility Name
Site 3003
City
Bern
ZIP/Postal Code
3010
Country
Switzerland
Facility Name
Site 3004
City
Geneva
ZIP/Postal Code
1211
Country
Switzerland
Facility Name
Site 3002
City
Zürich
ZIP/Postal Code
8091
Country
Switzerland

12. IPD Sharing Statement

Learn more about this trial

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

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