Complement Inhibition: Attacking Overshooting inflammation @fter Subarachnoid Hemorrhage (CIAO@SAH trial)

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. Inhibiting of the complement system is
therefore considered to be a potentially important new treatment for SAH. In
this study we will investigate 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.

This study has been transitioned to CTIS with ID 2025-520540-15-00 check the CTIS register for the current data.

Primary Objective: To determine the safety and efficacy of 6000 IU C1-INH in
patients with subarachnoid hemorrhage (SAH)

Primary hypothesis: The hypothesis is that random assignment to C1-INH in SAH
will lead to a reduction in delayed cerebral ischemia (DCI) compared to random
assignment to placebo. Furthermore, to access safety, no difference should be
detected in complication rate during hospitalization between the two groups

Secondary Objective: To determine differences between C1-INH and placebo
treatment in the following outcomes for patients with SAH:
- Clinical outcomes: cerebral infarction on brain CT/MRI, mortality, hospital
and ICU length of stay, ventilator days, hospital disposition, functional
outcome (mRS, GOSE and BI), cognitive function (MoCA/TICS-M) and
quality of life (EQ-5D-5L)
- Neurological damage: BANYAN (GFAP/UCHL-1) blood biomarker
- Complement activation: human serum (WIESLAB assay), total terminal complement
activity levels (CH50) and protein levels of complement
component (C3b/C, C4b/C and C5b-9) in plasma and CSF
- Coagulation cascade activation (PT, aPPT, PLT, D-dimer, fibrinogen)
- Inflammatory markers in serum and CSF (TNF-alpha, intraleukin)
- Level of C1-inhibitor activity in plasma and CSF

The proposed trial is a prospective, multicenter, randomized, double-blind,
placebo-controlled phase II trial, with one group receiving one dose of C1-INH
intravenously (IV) and one group receiving a placebo injection IV. The study
will be performed in Haaglanden Medical Center and Amsterdam University Medical
Center. During a two-year period, patients diagnosed with SAH on admission to
the emergency departments will be eligible for inclusion. If informed consent
can be obtained within 12 hours after ictus, patients are randomly assigned to
one of the two study arms and will receive a single dose of 6000 IU C1-INH or
placebo IV. (1 IU = the average endogenous level C1-esterase inhibitor in 1 ml
human plasma). Neither the participants, nor the experimenters will know who is
receiving the C1-INH or placebo. All patients will receive standard care. Blood
and CSF samples (CSF when an external ventricular drain (EVD) is placed) will
be taken from both patient groups before administration of C1-INH or placebo.
Additional blood samples will be taken at 6, 12, 24, 48, 72, 96 hours after
dosing of the C1-INH or placebo. An additional CSF sample will be taken at 24
hours after dosing of the C1-INH or placebo if a EVD is placed. The timing of
these samples is based on the estimated activity and elimination time of the
test compound and the timing of the onset of neuroinflammation and complement
activation described in previous literature. Blood and CSF samples will be used
to measure qualitative levels of functional classical, MBL and alternative
complement pathways in human serum, total terminal complement activity levels,
protein levels of complement component using different assays and additional
inflammatory markers like TNF-alpha and intraleukin. Patients will receive
routine CT scans as part of the standard care.

Clinical scores routinely used in the standard clinical care and follow-up
during recovery of SAH will be registered up six months after ictus as part of
the standard follow-up for SAB.

Informed/deferred consent must be obtained within 12 hours as the efficacy of
the C1-INH is suspected to be limited 12 hours after ictus. The HMC will
function as a data coordination and analysis center. All neurosurgeons,
intensive care physicians/nurses and other people concerned will be instructed
with regard to the study.

- Cinryze (6000 IU): Cinryze is a C1 esterase inhibitor derived from human
plasma. The primary function of Cinryze is to regulate the activation of the
complement pathways. This regulation is done by inactivation of Cl which
prevents Cir and Cis from binding. These two enzymes are required for
activation of the classical complement pathway. In addition, it regulates the
intrinsic coagulation pathway through inactivation of kallikrein and factor
Xlla. Without this inhibitor, activation of these pathways leads to the
production of peptide bradykinin. Therefore, Cinryze is approved for the
treatment of angioedema attacks in adults and children with hereditary
angioedema (HAE). This is a hereditary disease in which swelling develops
attack-like. There is currently no indication for Cinryze in patients with
subarachnoidal haemorrhage (SAH). This study will determine whether Cinryze
suppresses the complement system enough. With good results, further brain
damage and serious unforeseen events in the treatment of future patients with
subarachnoid hemorrhage (SAH) can be prevented.

- Placebo: 0.9% NaCI in the same dose as Cinryze

The treatment itself consists out of a single intravenous injection (6000 IU)
C1-INH or equal injection volume of placebo (physiological saline. C1-INH is a
C1 esterase inhibitor isolated from human plasma. As such it is a *human blood
product* and cannot be used by people sensitive for human blood products. When
medicinal products prepared from human blood or plasma are administered, the
possibility of transmitting infective agents cannot be totally excluded. This
also applies to unknown or emerging viruses and other pathogens. Nevertheless,
this risk is considered very low. The risks associated with short term
complement inhibition by C1-INH are a theoretical increase in susceptibility
for bacterial meningitis. This is controlled in this study by the short term of
the treatment with complement inhibitors and careful monitoring of the patient
for such infections. This risk is considered low. A decrease in coagulation
time because of C1-INH treatment is possible. This can result in thrombosis and
might pose extra risks in patients with indwelling catheters. Since the drug is
given only once this risk is considered low and patients with a known history
of thrombosis will be excluded. The safety profile of C1-INH has widely been
investigated in different clinical trials and is excellent.