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

Anakinra in Cerebral Haemorrhage to Target Secondary Injury Resulting From Neuroinflammation - a Phase II Clinical Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Intracerebral Hemorrhage
• Intervention / Treatment: Drug: Anakinra

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Floris H.B.M Schreuder, MD PhD; Phone Number: +31650155755; Email: floris.schreuder@radboudumc.nl
• Study Contact Backup: Name: Maaike P. Cliteur, MD; Phone Number: +31650155723; Email: maaike.cliteur@radboudumc.nl

Study Locations

• Netherlands
  • Nijmegen, Netherlands
    • Recruiting
    • Radboudumc
    • Contact: Radboudumc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perihematomal oedema	Measured as Oedema Extension Distance (OED/EED)	7 days after ICH onset

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events of special interest (AESI) and serious adverse events (SAE)		90 days
Blood brain barriere leakage	Measured as Ktrans on DCE-MRI	7 days
Levels of serum inflammatory markers	IL-1β, IL-6, hsCRP, neutrophil and total white blood cell counts	7 days
Functional outcome	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.	90 days

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Dutch Heart Foundation

Publications and helpful links

General 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. 2023 Sep 15:23969873231200686. doi: 10.1177/23969873231200686. Online ahead of print.

Helpful Links

• trial website

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2022
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: March 29, 2021
• First Submitted That Met QC Criteria: April 2, 2021
• First Posted (Actual): April 8, 2021

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: NL76607.091.21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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