This study has been transitioned to CTIS with ID 2024-517230-17-00 check the CTIS register for the current data. To determine the effect of anakinra on the development of perihematomal oedema, compared to standard medical management. In an…
ID
Source
Brief title
Condition
- Central nervous system vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome is effect anakinra compared to standard medical care on
perihematomal oedema (measured as oedema extension distance on MRI at day 7).
Secondly, we will compare the effect on oedema extension distance of the high
dose versus the low dose anakinra groups.
Secondary outcome
Secondary study parameters are to determine whether anakinra alters the level
of serum inflammation markers and the blood barrier leakage Ktrans as measured
with DCE-MRI on day 7. Furthermore to determine the safety profile of anakinra
in sICH and to test whether it influences the clinical outcome in sICH at 90
days.
Background summary
Spontaneous intracerebral haemorrhage yearly affects over 6000 patients in the
Netherlands. It is the deadliest stroke subtype, with a 30-day case-fatality of
40%. Of patients surviving, only few gain independence. However, effective
treatment options are still lacking. This is reflected in the prognosis which
has not improved over the last 30 years. Inflammation is known to play a vital
role in the development of secondary brain injury related to intracranial
haemorrhage. The release of blood products in the brain parenchyma leads to an
activation of the immune system. This subsequently leads to destruction of the
blood brain barrier and the formation of perihematomal oedema. Among the
released cytokines, interleukin 1 beta (IL-1β) has a pivotal role. IL-1β is
antagonized by the naturally occurring interleukin-1 receptor antagonist
(IL-1Ra) through competitive binding to the IL-1 receptor. Recombinant human
IL-1Ra (anakinra) is available for treatment of rheumatoid arthritis, other
inflammatory diseases and has been studied in acute sepsis. We hypothesize that
anakinra safely reduces SBI after sICH, and that is effect is dose-dependent.
Study objective
This study has been transitioned to CTIS with ID 2024-517230-17-00 check the CTIS register for the current data.
To determine the effect of anakinra on the development of perihematomal oedema,
compared to standard medical management. In an exploratory analysis, we will
investigate whether this effect is dose-dependent. Furthermore, to study its
effect on serum inflammatory markers, increased blood-brain-barrier leakage and
functional outcome in patients with sICH.
Study design
Multicentre, prospective, randomized, three-armed (1:1:1) trial with open label
treatment and blinded end-point assessment (PROBE design) of IL-1Ra (anakinra).
Intervention:
Patients will receive anakinra in either a high dose (loading dose 500mg i.v.,
followed by infusion with 2mg/kg/h over 3 days) or in a low dose (loading dose
100mg s.c., followed by subcutaneous administration of 100mg twice a day for 3
days), started within 8 hours of symptom onset. The control group will receive
standard medical management.
Study burden and risks
IL-1Ra has been evaluated in many clinical trials and is well tolerated with a
consistent safety profile. Treatment duration will just be 3 days, therefore
avoiding the risks associated with longterm use of anakinra such as neutropenia
and increased infection risk. Patients will be treated in a clinical setting on
a specialized stroke unit where they can be monitored frequently. During the
first 7 days of this study protocol patients will undergo blood sample
collection (day 0, 1, 3 and 7) and a DCE-MRI-scan (day 7±1) which includes
administration of gadolinium-based contrast (duration ±40 minutes). The risk of
these procedures are negligible and the burden is considered low. Functional
outcome at 3 months will be assessed via telephone. Taken together, we expect
the risk and burden of participation for individual patients to be low. As we
hypothesize that IL-1Ra could ameliorate perihaematomal oedema, which is
associated with a poor functional outcome, individual patients might benefit
from participation in this trial. Furthermore, this study will contribute to
important insights into the therapeutic potential of anakinra in sICH and its
safety profile on group level.
Reinier Postlaan 4
Nijmegen 6525 GC
NL
Reinier Postlaan 4
Nijmegen 6525 GC
NL
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years;
2. Supratentorial non-traumatic ICH confirmed by CT, without a confirmed
causative lesion on admission CT-angiography (e.g. aneurysm, AVM, DAVF,
cerebral venous sinus thrombosis) or other known underlying lesion (e.g.
tumour, cavernoma);
3. Minimal intracerebral haemorrhage volume of 10 mL
4. Intervention can be started within 8 hours from symptoms onset;
5. Patient*s or legal representative*s informed consent.
Exclusion criteria
1. Severe ICH, unlikely to survive the first 72 hours (defined as Glasgow Coma
Scale score < 6 at time of consent);
2. Confirmed or suspected haemorrhagic transformation of an arterial or venous
infarct;
3. Planned neurosurgical haematoma evacuation;
4. Severe infection at admission, requiring antibiotic treatment;
5. Known active tuberculosis or active hepatitis;
6. Use of immunosuppressive or immune-modulating therapy at admission (see 15.1
Appendix A);
7. Neutropenia (Absolute Neutrophil Count (ANC) <1.5 x 109/L );
8. Pre-stroke modified Rankin Scale score >= 3;
9. Pregnancy or breast-feeding;
10. Standard contraindications to MRI;
11. Known prior allergic reaction to gadolinium contrast or one of the
constituents of its solution for administration;
12. Known allergy to anakinra or other products that are produced by DNA
technology using the micro-organism E. coli;
13. Vaccinations with live attenuated microorganisms within the last 10 days
prior to this ICH;
14. Severe renal impairment (eGFR <30ml/min/1.73m);
15. Known active malignancy
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 |
|---|---|
| EU-CTR | CTIS2024-517230-17-00 |
| EudraCT | EUCTR2021-000324-36-NL |
| ClinicalTrials.gov | NCT04834388 |
| CCMO | NL76607.091.21 |