This study aims to investigate the biological efficacy and safety of eculizumab in patients with aneurysmal SAH.
ID
Source
Brief title
Condition
- Central nervous system vascular disorders
- Aneurysms and artery dissections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome measure is biological effectivity determined by the
concentration of C5a in CSF.
Secondary outcome
The secondary outcome measures are the occurrence of adverse events (AEs) and
serious adverse events (SAEs), plasma and CSF parameters of inflammation,
quality of life (QoL), functional, and cognitive outcomes, and the presence and
volume of cerebral infarction.
Background summary
Important determinants of poor functional outcome after aneurysmal SAH are
early brain injury (brain injury <72 hours after ictus) and delayed cerebral
ischemia (4-14 days after the bleeding). No treatment exists to reduce early
brain injury and the effects of current strategies (nimodipine, euvolemia) to
prevent delayed cerebral ischemia are only modest. The inflammatory response is
considered to play a key role in the pathogenesis of early brain injury and
delayed cerebral ischemia after aneurysmal SAH. Previous studies found that the
complement cascade is activated in patients with SAH and associated with poor
functional outcome. Recent research shows that brains of patients who died from
aneurysmal SAH had much higher complement expression than brains from controls.
In a mouse model of SAH, treatment of mice with C5 antibodies resulted in a
decrease in brain injury compared to mice without treatment. We hypothesize
that treatment with C5 antibodies decreases early brain injury and delayed
cerebral ischemia in patients with aneurysmal SAH and thereby improves clinical
condition. In the current trial, we will investigate the biological effect and
safety of eculizumab (C5 antibodies) in patients with aneurysmal SAH.
Study objective
This study aims to investigate the biological efficacy and safety of eculizumab
in patients with aneurysmal SAH.
Study design
This will be a randomized, open-label phase II clinical trial with blinded
outcome assessment. Patients admitted to the hospital within <=11.5 hours after
ictus and patients with a confirmed aneurysmal subarachnoid hemorrhage are
eligible for this study. Informed consent will be obtained from the patient or
a legally acceptable surrogate (if the patient is incapacitated). In case the
patient was incapacitated at admission, the patient will be asked for informed
consent as soon as the patient can give informed consent. This will be checked
daily by the treating physician or investigator. If the patient or a legally
accepted surrogate gives informed consent, randomization starts. The outcome of
the randomization will either be 'eculizumab treatment and care as usual' or
only 'care as usual'. Depending on the outcome, eculizumab will be administered
(as soon as possible but not later than 12 hours after ictus) in addition to
the standard care or only standard care will be given.
Intervention
The intervention group will receive intravenous eculizumab infusions. The
control group will receive standard treatment for SAH (no placebo).
Study burden and risks
Risks associated with eculizumab:
Eculizumab has been approved for treatment of patients with Paroxysmal
Nocturnal Hemoglobinuria (PNH) and Atypical Hemolytic Uremic Syndrome (aHUS).
The most common AE reported during treatment with eculizumab is headache
(occurred mostly in the initial phase). Patients who are treated with
eculizumab show an increased susceptibility to infections, especially to
infections with the meningococcus bacteria. To address the increased risk of
meningococcal infection, patients in the intervention group will receive
prophylactic treatment with ciprofloxacin during the first four weeks after
ictus. In addition, throat- and rectal swaps will be performed weekly in all
patients in the intervention group to test for carriership/colonization (yeast)
and to determine drug-resistance (multi-drug resistance bacteria and yeast).
Patients in the intervention group with a central line/drain and a positive
swap will receive antifungal prophylaxis next to the antibiotic prophylaxis. If
drug resistance occurs, prophylactic therapy will be adjusted in consultation
with the microbiologist. Before discharge, patients in the intervention group
will receive safety instructions and a patient safety card. These patients will
be asked to carry the patient safety card on their person until three months
after the last administration of the study drug. The control group will not
receive antibiotics or antifungal therapy.
Risks associated with study procedures:
Complications of CSF withdrawal from an external ventricular or lumbar drain
include a possible increased risk of infection. If CSF withdrawal from a drain
is not possible, a lumbar puncture will be performed. Potential risks consist
of a lumbar puncture are: 1) post-lumbar puncture headache; 2) back pain and;
3) radicular pain or numbness. Very rare complications of a lumbar puncture
include: 1) infection; 2) bleeding; and 3) abducens palsy. Withdrawal of blood
poses very minor risks including bruising, pain, swelling and redness, possible
infection at the injection site, and a rare risk of fainting. There is no
increased risk for any of the other examinations performed (e.g. daily
neurological examination, throat- and rectal swaps, magnetic resonance imaging
(MRI) without gadolinium, cognitive-, QoL, and modified Ranking scale testing).
Risks associated with antibiotic use (only for the intervention group) and if
necessary antifungal prophylaxis (only in the intervention group in patients
with a central line/drain and a positive swap)
A potential risk of antibiotic/antifungal therapy is resistance. With throat-
and rectal swaps, we will closely monitor drug resistance. In case a patient
develops drug resistance, the microbiologist will be consulted to discuss other
options for prophylaxis. We exclude patients with a high risk of drug resistant
bacteria or yeast. Potential side-effects of antibiotic use are described in C1
' Onderzoeksprotocol' and the E1/E2 *Patient information letter*.
Potential benefits:
Benefits from treatment with eculizumab include a potential decrease in brain
injury (from early brain injury and delayed cerebral ischemia) and hereby a
better prognosis.
Heidelberglaan 100
Utrecht 3508 GA
NL
Heidelberglaan 100
Utrecht 3508 GA
NL
Listed location countries
Age
Inclusion criteria
1) Confirmed aneurysmal subarachnoid hemorrhage (SAH)
2) Admission to either the UMCU or Erasmus MC within 11.5 hours after ictus
3) Age 18 years and older
Exclusion criteria
1) Life expectancy < 10 days;
2) Pregnant or breast-feeding women;
3) Participation in another clinical therapeutic study;
4) History of splenectomy or asplenia (potentially increased risk of
meningococcal infection);
5) Hematologic malignancy;
6) Patients receiving chemotherapy;
7) Patients who will undergo or underwent an organ transplantation;
8) Patients with myasthenia gravis, glucose-6-phosphate dehydrogenase
(G6PD) deficiency, or tuberculosis;
9) Patients who are or will be treated by plasmapheresis or
hemodialysis;
10) Patient with a creatinine clearance of <30 or serum creatinine levels
of >169 µmol/l
11) Patients with a known hereditary complement deficiency;
12) Patients allergic to eculizumab, proteins derived from mouse
products or other monoclonal antibodies;
13) Patients allergic to (prophylactic) antibiotic treatment for Neisseria
meningitidis (quinolones or ceftriaxone (therapeutic));
14) If on admission, it is likely that the aneurysm can only be treated
with extracranial-intracranial bypass surgery;
15) If based on head imaging, it will be unlikely that CSF can be obtained
48-72 hours after ictus;
16) Patients with an ongoing infection on admission which is not
appropriately treated;
17) Patients who were treated >4 times with antibiotics during the last
year;
18) Patients on immunosuppressive therapy.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-004307-51-NL |
| CCMO | NL63723.041.17 |