Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial

Abstract

Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of IL1ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rhIL1ra-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time.

Figures

Figure 1

Cerebral microdialysate and plasma interleukin-1 receptor antagonist (IL1ra) concentration and study time line. (A) Cerebral microdialysate concentration of IL1ra in control (blue) and intervention (red) patients. Error bars denote standard error of the mean. (B) Study time line. After recruitment to the study, patients were monitored for 6 hours (microdialysis time point 1), as a baseline, before administration of 100 mg recombinant human IL1ra (rhIL1ra) by subcutaneous injection daily for 5 days in the intervention group (10 patients) or no drug in the control group (10 patients). Microdialysis monitoring continued throughout with samples pooled into 6 hour time epochs with a total of 20 samples. Plasma sampling was performed 1 hour before and 1 hour after drug administration, giving a total of 10 samples. In control patients, these plasma samples were taken in relation to the hypothetical time at which the drug would have been administered in an identical manner to the intervention patients. (C) Plasma concentrations of IL1ra in control (blue) and intervention (red) patients. Mean IL1ra±standard error of the mean is plotted on a logarithmic scale. Plasma samples were taken 1 hour before and 1 hour after drug administration.

Figure 2

Principal component analysis (PCA) shows a difference in cytokine profile after rhIL1ra administration. (A) PCA of all microdialysis cytokine observations. Each data point on the plot denotes a single sample (6 hourly) from a single patient assayed for each of the 42 cytokines. Data points are colored by the patient randomization group as control (blue) and intervention (red). (B) Loading plot corresponding to the scores plot in panel A showing the cytokines loading on the principal component (PC) axes. The two PCs of the model explain 43% of the variation in the data set (R2X). EGF, epidermal growth factor; FGF2, basic fibroblast growth factor; Flt3 lig, Fms-related tyrosine kinase 3 ligand; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte-monocyte colony stimulating factor; IFNa2, interferon alpha-2; IFNg, interferon gamma; IL, interleukin; IL-1R, interleukin 1 receptor; IL1ra, interleukin-1 receptor antagonist; IL12p40, interleukin 12 subunit beta; IL12p70, interleukin-12; IP10, chemokine (C-X-C motif) ligand 10; MCP, monocyte chemotactic protein; MDC, macrophage-derived chemoattractant; MIP1a, macrophage inflammatory protein-1alpha; MIP1b, macrophage inflammatory protein-1beta; PDGF, platelet-derived growth factor; sCD40L, soluble CD40 ligand; sIL2R, soluble interleuking-2 receptor; TGFa, transforming growth factor alpha; TNFa, tumor necrosis factor alpha; TNFb, tumor necrosis factor beta; VEGF, vascular endothelial growth factor. CSF, cerebrospinal fluid.