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

• ClinicalTrials.gov Identifier: NCT04834388
• Recruitment Status: Recruiting
• First Posted: April 8, 2021
• Last Update Posted: November 30, 2023
• Sponsor: Radboud University Medical Center
• Collaborator: Dutch Heart Foundation
• Information provided by (Responsible Party): Radboud University Medical Center

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
Intracerebral Hemorrhage	Drug: Anakinra	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: PROBE 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: August 10, 2022
• Estimated Primary Completion Date: September 2024
• Estimated Study Completion Date: December 2024

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 Name: 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 Name: Kineret
No Intervention: Standard care; Standard care group

Outcome Measures

Primary Outcome Measures :

1. Perihematomal oedema [ Time Frame: 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) [ Time Frame: 90 days ]
2. Blood brain barriere leakage [ Time Frame: 7 days ]
   Measured as Ktrans on DCE-MRI
3. Levels of serum inflammatory markers [ Time Frame: 7 days ]
   IL-1β, IL-6, hsCRP, neutrophil and total white blood cell counts
4. Functional outcome [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts

Contact: Floris H.B.M Schreuder, MD PhD; +31650155755; floris.schreuder@radboudumc.nl

Contact: Maaike P. Cliteur, MD; +31650155723; maaike.cliteur@radboudumc.nl

Locations

Netherlands

Radboudumc; Recruiting

Nijmegen, Netherlands

Contact: Radboudumc

Sponsors and Collaborators

Radboud University Medical Center

Dutch Heart Foundation

More Information

Additional Information:

trial website 

Publications:

Cliteur MP, van der Kolk AG, Hannink G, Hofmeijer J, Jolink W, Klijn C, Schreuder F. Anakinra in cerebral haemorrhage to target secondary injury resulting from neuroinflammation (ACTION): Study protocol of a phase II randomised clinical trial. Eur Stroke J. 2024 Mar;9(1):265-273. doi: 10.1177/23969873231200686. Epub 2023 Sep 15.

• Responsible Party: Radboud University Medical Center
• ClinicalTrials.gov Identifier: NCT04834388
• Other Study ID Numbers: NL76607.091.21
• First Posted: April 8, 2021
• Last Update Posted: November 30, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• 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:

Cerebral Hemorrhage; Hemorrhage; Pathologic Processes; Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Interleukin 1 Receptor Antagonist Protein; Antirheumatic Agents