Clinical trial NCT00111085: Clazosentan in Preventing the Occurrence of Cerebral Vasospasm Following an Aneurysmal Subarachnoid Hemorrhage (aSAH)
Official title: A Phase IIb, Multi-center, International, Double-blind, Randomized, Placebo-controlled, Parallel-group, Dose-finding Study for the Prevention of Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage (aSAH) by Intravenous Administration of Clazosentan, a Selective Endothelin A (ETA) Receptor Antagonist
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aneurysmal Subarachnoid Hemorrhage
Keywords: delayed ischemic neurological deficits (DIND)
vasospasm
clazosentan
cerebral vasospasm
computer tomography scan (CT scan)
digital subtraction angiography (DSA)
endothelin A receptor
aneurysmal subarachnoid hemorrhage (aSAH)
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2005-05-18
Enrollment: 413
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: The purpose of the study is to measure how effective and safe three different doses of the drug clazosentan are in preventing vasospasm after subarachnoid hemorrhage.


Eligibility criteria: Inclusion criteria:

1. Male or female patients aged 18 to 70 years (inclusive) or male patients aged 45 to 70 (inclusive) or males aged 18 to 44 (inclusive) who are surgically or naturally sterile or can personally sign the core Informed Consent
2. Patients with a ruptured saccular aneurysm that has been confirmed by digital subtraction angiography (DSA) and for which clipping or coiling (endovascular obliteration) is possible.
3. Patients with a diffuse or localized thick subarachnoid clot on baseline CT scan. Measurements defining clot thickness and extension are as follows: Diffuse: Clot with long axis \>= 20 mm, or any clot if present in both hemispheres Localized: Clot with long axis \< 20 mm Thick: Clot with short axis \>= 4 mm Thin: Clot with short axis \< 4 mm
4. Start of screening within 48 hours post onset of aSAH clinical symptoms
5. World Federation of Neurological Surgeons (WFNS) Grades I-IV, and those Grade V patients who improve to Grade IV or less after ventriculostomy
6. In the case of multiple aneurysms, the aneurysm that has ruptured is identified with a high likelihood during the screening period
7. Women of childbearing potential with pre-treatment negative serum pregnancy test
8. Patient is able to start the study drug infusion within 56 hours after the rupture of the aneurysm, and the procedure option (clipping or coiling) must either be started within a maximum of 12 hours after the start of study drug infusion or should have been already performed
9. Written informed consent to participate in the study must be obtained from the patient or a legal representative prior to initiation of any study-related procedure and enrollment

Exclusion criteria:

1. Patients with SAH due to other causes (e.g., trauma or rupture of fusiform or mycotic aneurysms)
2. Patients with intraventricular or intracerebral blood, in the absence of subarachnoid blood
3. No visualized clot or presence of only localized thin clot on CT (\< 20 mm x 4 mm)
4. Presence of any degree of cerebral vasospasm on screening angiogram
5. Patients with hypotension (systolic blood pressure (SBP) \<=90 mmHg) refractory to fluid therapy
6. Patients with neurogenic pulmonary edema or severe cardiac failure requiring inotropic support
7. Any severe or unstable concomitant condition or disease (e.g., known significant neurological deficit, cancer, hematological, or coronary disease), or chronic condition (e.g., psychiatric disorder) which, in the opinion of the Investigator, would affect the assessment of the safety or efficacy of the study drug
8. Advanced kidney and/or liver disease, as defined by plasma creatinine \>=2 mg/dl (177 micromol/l) and/or total bilirubin \> 3 mg/dl (51.3 micromol/l)
9. Any known or CT evidence of previous major cerebral damage (e.g., stroke \[\> 2 cm\], traumatic brain injury \[\> 2 cm\], previously treated cerebral aneurysm, arterial venous malformation \[AVM\]), or other preexisting cerebrovascular disorders, which may affect accurate diagnosis and evaluation of SAH
10. Patients receiving prophylactic i.v. nimodipine or i.v. nicardipine. If present, these must be stopped at least 4 hours prior to initiation of the study treatment
11. Patients who have received thrombolytics, including intracisternal administration, intrathecal treatments and therapeutic hypothermia for treatment of the SAH
12. Patients who have received an investigational product within 28 days prior to randomization
13. Patients with current alcohol or drug abuse or dependence

Primary outcomes:
measure: Occurrence of moderate or severe cerebral vasospasm, as measured by cerebral angiography
timeFrame: Up to day 14
Secondary outcomes:
measure: Occurrence of vasospasm-related morbidity, and mortality of all causes defined as the occurrence of death of any cause within the first 6 weeks post-aneurysm rupture OR
timeFrame: Within 6 weeks
measure: Occurrence of vasospasm-related morbidity, and mortality of all causes defined as the occurence of new cerebral infarct within first 6 weeks post-aneurysm rupture based on local investigator reading of post-baseline CT scans OR
timeFrame: Within 6 weeks
measure: Occurrence of vasospasm-related morbidity, and mortality of all causes defined as the occurence of delayed ischemic neurological deficits (DIND) due to vasospasm (based on investigator assessments) within 14 days post-aneurysm rupture OR
timeFrame: Within 14 days
measure: Occurrence of vasospasm-related morbidity, and mortality of all causes defined as occurrence of use of rescue medication due to vasospasm within 14 days post-aneurysm rupture
timeFrame: Within 14 days
measure: Clinical outcome at 12 weeks post-aneurysm rupture as measured by the Modified Rankin Scale (mRS) score
timeFrame: At 12 weeks
measure: Clinical outcome at 12 weeks post-aneurysm rupture as measured bythe Glasgow Outcome Scale - Extended Version (GOSE) score
timeFrame: At 12 weeks
Other outcomes:
Locations:
city: Peoria
country: United States
facility: Dr. Giuseppe Lanzino
state: Illinois
city: Indianapolis
country: United States
facility: Dr. Horner
state: Indiana
city: Baltimore
country: United States
facility: Dr. Aldrich
state: Maryland
city: Boston
country: United States
facility: Dr. Ogilvy
state: Massachusetts
city: Cincinnati
country: United States
facility: Dr. Zuccarello
state: Ohio
city: Cleveland
country: United States
facility: Dr. Woo
state: Ohio
city: Philadelphia
country: United States
facility: Dr. Rosenwasser
state: Pennsylvania
city: Philadelphia
country: United States
facility: Dr. Zager
state: Pennsylvania
city: Houston
country: United States
facility: Dr. George A. Lopez
state: Texas
city: Richmond
country: United States
facility: Dr. Bullock
state: Virginia
city: Calgary
country: Canada
facility: Dr. Wong
state: Alberta
city: Edmonton
country: Canada
facility: Dr. Findlay
state: Alberta
city: Vancouver
country: Canada
facility: Dr. Redekop
state: British Columbia
city: Toronto
country: Canada
facility: Dr. Ferguson
state: Ontario
city: Montreal
country: Canada
facility: Dr. Bojanowski
state: Quebec
city: Halifax, Nova Scotia
country: Canada
facility: Dr. Fleetwood
Study officials:
References:
citation: Eagles ME, Powell MF, Ayling OGS, Tso MK, Macdonald RL. Acute kidney injury after aneurysmal subarachnoid hemorrhage and its effect on patient outcome: an exploratory analysis. J Neurosurg. 2019 Jul 12;133(3):765-772. doi: 10.3171/2019.4.JNS19103. Print 2020 Sep 1.
citation: Ayling OGS, Ibrahim GM, Alotaibi NM, Gooderham PA, Macdonald RL. Anemia After Aneurysmal Subarachnoid Hemorrhage Is Associated With Poor Outcome and Death. Stroke. 2018 Aug;49(8):1859-1865. doi: 10.1161/STROKEAHA.117.020260.
citation: Ayling OG, Ibrahim GM, Alotaibi NM, Gooderham PA, Macdonald RL. Dissociation of Early and Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage. Stroke. 2016 Dec;47(12):2945-2951. doi: 10.1161/STROKEAHA.116.014794. Epub 2016 Nov 8.
citation: Nassiri F, Ibrahim GM, Badhiwala JH, Witiw CD, Mansouri A, Alotaibi NM, Macdonald RL. A Propensity Score-Matched Study of the Use of Non-steroidal Anti-inflammatory Agents Following Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care. 2016 Dec;25(3):351-358. doi: 10.1007/s12028-016-0266-6.
citation: Tso MK, Ibrahim GM, Macdonald RL. Predictors of Shunt-Dependent Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage. World Neurosurg. 2016 Feb;86:226-32. doi: 10.1016/j.wneu.2015.09.056. Epub 2015 Sep 30.
citation: Young JM, Morgan BR, Misic B, Schweizer TA, Ibrahim GM, Macdonald RL. A Partial Least-Squares Analysis of Health-Related Quality-of-Life Outcomes After Aneurysmal Subarachnoid Hemorrhage. Neurosurgery. 2015 Dec;77(6):908-15; discussion 915. doi: 10.1227/NEU.0000000000000928.
citation: Ibrahim GM, Macdonald RL. The network topology of aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2015 Aug;86(8):895-901. doi: 10.1136/jnnp-2014-308992. Epub 2014 Oct 3.
citation: Ibrahim GM, Morgan BR, Macdonald RL. Patient phenotypes associated with outcomes after aneurysmal subarachnoid hemorrhage: a principal component analysis. Stroke. 2014 Mar;45(3):670-6. doi: 10.1161/STROKEAHA.113.003078. Epub 2014 Jan 14.
citation: Ibrahim GM, Fallah A, Macdonald RL. Clinical, laboratory, and radiographic predictors of the occurrence of seizures following aneurysmal subarachnoid hemorrhage. J Neurosurg. 2013 Aug;119(2):347-52. doi: 10.3171/2013.3.JNS122097. Epub 2013 Apr 12.
citation: Ibrahim GM, Macdonald RL. Electrocardiographic changes predict angiographic vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2012 Aug;43(8):2102-7. doi: 10.1161/STROKEAHA.112.658153. Epub 2012 Jun 7.
citation: Ibrahim GM, Weidauer S, Vatter H, Raabe A, Macdonald RL. Attributing hypodensities on CT to angiographic vasospasm is not sensitive and unreliable. Stroke. 2012 Jan;43(1):109-12. doi: 10.1161/STROKEAHA.111.632745. Epub 2011 Oct 13.