Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH)

Adrian R Parry-Jones; Katie Stocking; Mary Joan MacLeod; Brian Clarke; David J Werring; Keith W Muir; Andy Vail

doi:10.1177/23969873231185208

Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH)

Adrian R Parry-Jones^* (Corresponding Author), Katie Stocking, Mary Joan MacLeod, Brian Clarke, David J Werring, Keith W Muir, Andy Vail

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Purpose: Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers.
Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100?mg subcutaneous anakinra within 8?h of onset, followed by five, 12-hourly, 100?mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72?h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6).
Findings: 25 patients (target?=?80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6?ml, interquartile range[IQR]:4.8?17.9) versus placebo (5.5?ml, IQR:2.1?10.9). Adjusting for baseline, 72?h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: ?0.17?0.06, p?=?0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%?80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra.
Conclusion: We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required.

Original language	English
Pages (from-to)	819-827
Number of pages	9
Journal	European Stroke Journal
Volume	8
Issue number	3
Early online date	15 Jul 2023
DOIs	https://doi.org/10.1177/23969873231185208
Publication status	Published - Sept 2023

Bibliographical note

Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This report is independent research arising from a Clinician Scientist Award to APJ (CS-2014-14-005) supported by the National Institute for Health Research. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Anakinra (Kineret®) and placebo were provided free of charge by Swedish Orphan Biovitrum AB (publ) (Sobi) under an Investigator Initiated Study Agreement. Sobi was not involved in the design or conduct of the study, data collection and analysis, or preparation of the manuscript.

We are grateful to Sobi for supplying study drug and the NIHR Comprehensive Research Network and clinical teams at the BLOC-ICH sites. We are grateful to the members of the Trial Steering Committee and Independent Data Safety and Monitoring Committee (see Supplemental Materials for committee members).

Keywords

intracerebral hemorrhage
interleukin-1 receptor antagonist
anakinra
Clinical trial

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Cite this

Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH). / Parry-Jones, Adrian R (Corresponding Author); Stocking, Katie; MacLeod, Mary Joan et al.
In: European Stroke Journal , Vol. 8, No. 3, 09.2023, p. 819-827.

Research output: Contribution to journal › Article › peer-review

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title = "Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH)",

abstract = "Purpose: Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers.Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100?mg subcutaneous anakinra within 8?h of onset, followed by five, 12-hourly, 100?mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72?h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6).Findings: 25 patients (target?=?80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6?ml, interquartile range[IQR]:4.8?17.9) versus placebo (5.5?ml, IQR:2.1?10.9). Adjusting for baseline, 72?h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: ?0.17?0.06, p?=?0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%?80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra.Conclusion: We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required.",

keywords = "intracerebral hemorrhage, interleukin-1 receptor antagonist, anakinra, Clinical trial",

author = "Parry-Jones, {Adrian R} and Katie Stocking and MacLeod, {Mary Joan} and Brian Clarke and Werring, {David J} and Muir, {Keith W} and Andy Vail",

note = "Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This report is independent research arising from a Clinician Scientist Award to APJ (CS-2014-14-005) supported by the National Institute for Health Research. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Anakinra (Kineret{\textregistered}) and placebo were provided free of charge by Swedish Orphan Biovitrum AB (publ) (Sobi) under an Investigator Initiated Study Agreement. Sobi was not involved in the design or conduct of the study, data collection and analysis, or preparation of the manuscript. We are grateful to Sobi for supplying study drug and the NIHR Comprehensive Research Network and clinical teams at the BLOC-ICH sites. We are grateful to the members of the Trial Steering Committee and Independent Data Safety and Monitoring Committee (see Supplemental Materials for committee members).",

year = "2023",

month = sep,

doi = "10.1177/23969873231185208",

language = "English",

volume = "8",

pages = "819--827",

journal = "European Stroke Journal ",

issn = "2396-9873",

publisher = "Sage Publications",

number = "3",

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TY - JOUR

T1 - Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage

T2 - BLOcking the Cytokine IL-1 in ICH (BLOC-ICH)

AU - Parry-Jones, Adrian R

AU - Stocking, Katie

AU - MacLeod, Mary Joan

AU - Clarke, Brian

AU - Werring, David J

AU - Muir, Keith W

AU - Vail, Andy

N1 - Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This report is independent research arising from a Clinician Scientist Award to APJ (CS-2014-14-005) supported by the National Institute for Health Research. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Anakinra (Kineret®) and placebo were provided free of charge by Swedish Orphan Biovitrum AB (publ) (Sobi) under an Investigator Initiated Study Agreement. Sobi was not involved in the design or conduct of the study, data collection and analysis, or preparation of the manuscript. We are grateful to Sobi for supplying study drug and the NIHR Comprehensive Research Network and clinical teams at the BLOC-ICH sites. We are grateful to the members of the Trial Steering Committee and Independent Data Safety and Monitoring Committee (see Supplemental Materials for committee members).

PY - 2023/9

Y1 - 2023/9

N2 - Purpose: Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers.Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100?mg subcutaneous anakinra within 8?h of onset, followed by five, 12-hourly, 100?mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72?h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6).Findings: 25 patients (target?=?80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6?ml, interquartile range[IQR]:4.8?17.9) versus placebo (5.5?ml, IQR:2.1?10.9). Adjusting for baseline, 72?h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: ?0.17?0.06, p?=?0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%?80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra.Conclusion: We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required.

AB - Purpose: Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers.Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100?mg subcutaneous anakinra within 8?h of onset, followed by five, 12-hourly, 100?mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72?h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6).Findings: 25 patients (target?=?80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6?ml, interquartile range[IQR]:4.8?17.9) versus placebo (5.5?ml, IQR:2.1?10.9). Adjusting for baseline, 72?h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: ?0.17?0.06, p?=?0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%?80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra.Conclusion: We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required.

KW - intracerebral hemorrhage

KW - interleukin-1 receptor antagonist

KW - anakinra

KW - Clinical trial

U2 - 10.1177/23969873231185208

DO - 10.1177/23969873231185208

M3 - Article

C2 - 37452707

SN - 2396-9873

VL - 8

SP - 819

EP - 827

JO - European Stroke Journal

JF - European Stroke Journal

IS - 3

ER -

Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH)

Abstract

Bibliographical note

Keywords

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