ACTION: Studying Anakinra to Reduce Secondary Brain Damage After Spontaneous Haemorrhagic Stroke

Sponsor
Radboud University Medical Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT04834388
Collaborator
Dutch Heart Foundation (Other)
75
1
3
15.7
4.8

Study Details

Study Description

Brief Summary

Spontaneous intracerebral haemorrhage (sICH) is the deadliest stroke subtype yearly affecting over 6000 patients in the Netherlands. Treatment options are very limited. Inflammation plays a vital role in the development of sICH-related secondary brain injury (SBI). Within 4 hours after sICH onset, blood components and thrombin induce the release of cytokines and other inflammatory molecules, with subsequent microglial activation, blood brain barrier (BBB) damage and the formation of perihaematomal oedema (PHO). Among the released cytokines, interleukin 1 beta (IL-1β) has a pivotal role. Recombinant human interleukin-1 receptor antagonist (IL-1Ra, anakinra) effectively antagonizes IL-1β through competitive binding to the IL-1 receptor. 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 its effect is dose-dependent.

Objective: To determine the effect of high-dose versus low-dose anakinra compared to standard medical management on oedema extension distance (OED) determined with MRI on day 7±1. Second, to study the safety profile of anakinra. Furthermore, to assess its effect on 1) serum inflammatory markers IL-1β, IL-6, hsCRP, neutrophil and total white blood cell counts at day 1, 3 and 7 compared to baseline; 2) DCE-MRI measurement of BBB transfer constant (Ktrans) on day 7±1, and; 3) to estimate an effect on 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) .

Study population: 75 patients with supratentorial sICH admitted within 8 hours after symptom onset.

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; n=25) or in a low dose (loading dose 100mg s.c.., followed by subcutaneous administration of 100mg twice a day for 3 days; n=25), started within 8 hours of symptom onset. The control group (n=25) will receive standard medical management.

Main study parameters/endpoints: Primary objective is to test whether anakinra reduces subacute perihaematomal oedema after sICH, measured as OED on MRI at day 7±1.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Anticipated Enrollment :
75 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
PROBE designPROBE design
Masking:
Single (Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Anakinra in Cerebral Haemorrhage to Target Secondary Injury Resulting From Neuroinflammation - a Phase II Clinical Trial
Actual Study Start Date :
Aug 10, 2022
Anticipated Primary Completion Date :
Sep 1, 2023
Anticipated Study Completion Date :
Dec 1, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Anakinra High dose

500mg i.v. loading dose, followed by continuous iv infusion with 2mg/kg/h over 3 days

Drug: Anakinra
Anakinra treatment is started within 8 hours of symptom onset
Other Names:
  • Kineret
  • Experimental: Anakinra Low dose

    100mg s.c. loading dose, followed by subcuteanous administration of 100mg twice daily for 3 days.

    Drug: Anakinra
    Anakinra treatment is started within 8 hours of symptom onset
    Other Names:
  • Kineret
  • No Intervention: Standard care

    Standard care group

    Outcome Measures

    Primary Outcome Measures

    1. Perihematomal oedema [7 days after ICH onset]

      Measured as Oedema Extension Distance (OED/EED)

    Secondary Outcome Measures

    1. Adverse events of special interest (AESI) and serious adverse events (SAE) [90 days]

    2. Blood brain barriere leakage [7 days]

      Measured as Ktrans on DCE-MRI

    3. Levels of serum inflammatory markers [7 days]

      IL-1β, IL-6, hsCRP, neutrophil and total white blood cell counts

    4. Functional outcome [90 days]

      Ordinal shift in functional outcome (comparing the intervention group to the controls), assessed with the modified Rankin Scale (mRS) at 3 months. This is a six point scale in which a score of 0 means no symptoms at all, a higher score means more impairment, and a score of 6 means the participant is dead.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 (see 15.2 Appendix B);

    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. Live vaccinations within the last 10 days prior to this ICH;

    14. Severe renal impairment (eGFR <30ml/min/1.73m)

    15. Active malignancy

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Radboudumc Nijmegen Netherlands

    Sponsors and Collaborators

    • Radboud University Medical Center
    • Dutch Heart Foundation

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Radboud University Medical Center
    ClinicalTrials.gov Identifier:
    NCT04834388
    Other Study ID Numbers:
    • NL76607.091.21
    First Posted:
    Apr 8, 2021
    Last Update Posted:
    Aug 18, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 18, 2022