Subarachnoid Hemorrhage, Aneurysmal
Conditions
Brief summary
Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes for patients, like cognitive decline. This is caused by early brain injury (EBI) followed by delayed cerebral ischemia (DCI). Neuroinflammation, triggered by the complement system, has been investigated to be a key mediator in the pathophysiology of EBI and DCI. Inhibition of the complement system is therefore considered to be a potentially important new treatment for SAH. This trial aims to study the safety and efficacy of C1-inhibitor Cinryze, an approved inhibitor of the complement system, compared to placebo in patients with SAH. By temporarily blocking the complement system we hypothesize limitation of delayed cerebral ischemia and a more favourable clinical outcome for SAH patients due to a decrease in the inflammatory response.
Interventions
DRUGC1 Esterase Inhibitor Injection [Cinryze]
C1 Esterase Inhibitor Injection \[Cinryze\]
DRUGPlacebo
Sodium Chloride /physiological saline (0.9%) in equal volume dosed intravenous
Sponsors
Leiden University Medical Center
Takeda
Haaglanden Medical Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
A prospective, multicenter, randomized, double-blind, placebo-controlled, phase II trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of aneurysmal subarachnoid hemorrhage on CT-scan; * Age ≥ 18 years on admission; * WFNS grade 1-5.
Exclusion criteria
* Subarachnoid hemorrhage deemed most likely of 'peri mesencephalic' origin after consideration of history, clinical examination and radiological findings (including angiographic imaging); (not originated from an aneurysm and patients have by definition a favourable clinical outcome) * Subarachnoid hemorrhage deemed most likely of post-traumatic origin after consideration of history, clinical examination and radiological findings (including angiographic imaging); (does not occur spontaneous) * Participation in another clinical therapeutic study; * Patients with definite infaust prognosis on arrival and/or expected death within 24 hours of admission * Patients with a known hereditary complement deficiency (including hereditary angioedema); * Patients with a history of sensibility to blood products or C1-inhibitor; * Patients with a history of thrombosis (when known at time of inclusion); * Pregnant woman
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with delayed cerebral ischemia (DCI) | To be determined between day 4 and day 14 of admission | Defined as either a new focal neurological impairment, or a decrease of at least 2 points on the Glasgow Coma Scale. This should last for at least 1 hour, is not apparent immediately after aneurysm occlusion, and cannot be attributed to other causes by means of clinical assessment, CT or MRI scanning of the brain, and appropriate laboratory studies. |
| Number of participants with complications during hospitalization. | Up to 1 year after admission | Complication rate during hospitalization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neurological condition measured by Glasgow Coma Scale | During the first 14 days | Measured daily, minimum value of 3, maximal value of 15, higher scores mean a better outcome |
| Complement activity markers measured in serum and CSF | Before IV administration of C1-INH or placebo, and after 48 hours and 96 hours after IV administration | WIESLAB, C3b/C, C4b/C, C5b-9 ELISA assays, CH50/AC50 |
| Inflammatory markers measured in serum and CSF | Before IV administration of C1-INH or placebo, and after 48 hours and 96 hours after IV administration | TNF-alpha, intraleukins |
| Number of participants with cerebral infarction on brain CT | at 14 days after admission | — |
| Number of ICU days | Up to 1 year | ICU length of stay |
| Number of ventilator days | Up to 1 year | Ventilator days |
| Clinical outcome | At 6 months | Modified Ranking Scale, minimum value 0, maximum value 6, higher score means worse outcome |
| Number of days in the hospital | Up to 1 year | Hospital length of stay |
| Number of participants dying | Up to 1 year after admission | Mortality rate |
Countries
Netherlands
Contacts
Primary ContactDaan de Groot, MD
Outcome results
None listed