Shashank Shekhar, MD, MS
@Artofstroke

Smith CJ, Hulme S, Vail A, Heal C, Parry-Jones AR, Scarth S, et al. SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial. Stroke. 2018

Multiple preclinical and clinical research is suggesting the definite role of inflammation in the brain after ischemic stroke. The inflammation could be both detrimental and helpful based on the stages of the post-stroke pathogenesis. I always explain this to my stroke patients by giving an example of injury to, e.g., a finger. I ask them, When you hurt your finger, what happens to it? It starts hurting, swells and turns colors due to inflammation. Similarly, in the brain after stroke, the brain goes through the similar process; unlike pain medicine for fingers, we don’t have medicine which helps with inflammation in the brain, but with time, the body tends to heal most of the inflammation. Explaining to them in lay terms helps them understand the process better. In this study, investigators from the SCIL-Stroke phase II trial are investigating if blocking interleukin IL-1 results in the lowering IL-6 levels and if this could be associated with a better clinical outcome. This project is in line with the previously published work by Dr. Albers’ group, where they addressed a similar question but without a placebo control arm.

The study is a single-center, double-blinded, randomized placebo-controlled phase II trial performed in the UK. All patients were >18 years of age with confirmed ischemic stroke (NIHSS 4-26) and drug administered within 6 hours were eligible. The study screened 742 patients and recruited 63 patients (35 in placebo and 28 in treatment arm). The primary outcome was the area under the curve for the log-transformed concentration of plasma IL-6 between day 1-day 3. The secondary outcome was the clinical mRS (modified ranking score) at three months.

Results:

  • Baseline characteristic was similar in control and treatment arm except for slightly longer median onset to needle alteplase time in the treatment arm, and a higher rate of hypertension in the placebo arm.
  • IL-1Ra prevented the rise in plasma IL-6 in the placebo and significantly reduced the area under the curve plasma log (IL-6) in the adjusted linear regression analysis (P<0.001). Post-hoc sensitivity analysis, however, made no difference. A similar effect was noted with plasma CRP concentration.
  • There were a total of 16 serious adverse events in 14 patients (9 in placebo and 5 in IL-1Ra group). Serious events were neurological deterioration, pneumonia (9 both in the placebo arm), hemorrhagic transformation (2 in placebo and 3 in IL-1Ra), and respiratory attest (1 in placebo).
  • The mortality rates were similar in both arms.
  • The secondary clinical outcome showed 51% in the placebo and 42% in the treatment
  • Based on ordinal logistic regression analysis, IL-1 was not associated with favorable outcome in mRS.
  • However, mediation analysis suggested, IL1Ra improved odds of clinical outcome (lower mRS) via reducing IL-6 concentration (odds ratio [95% confidence interval] =0.42 [0.19-0.94]; p =0.04), but there was a negative residual effect with IL-1, increased the odds of poor mRS score (odds ratio 85% Ci = 4.48 (1.19-17.71) p =0.03 via some alternate pathway.

The author concluded IL-1Ra was safe, well-tolerated, and reduced circulating inflammatory markers associated with worse clinical outcome. However, a trend towards improved functional outcome at three months was offset by negative effect postulated via alternate IL1 receptor medicated or due to an interaction with the thrombolytic drug, alteplase. Numerous papers suggest the deleterious effect of alteplase (Wang X. et al., 2004, Stroke; Jicklings G.C. et al., 2014, J Cereb Blood Flow Metab), and numerous in vivo studies suggest by blocking the deleterious effect of alteplase results in a better outcome (Peña I.D. et al., 2017, J Stroke).

It would be interesting to the see the effect of IL-1Ra on a larger patient size. I believe that inflammation is multifaceted. Thus, we need to block inflammation at various targets only then we will be able to get a clinically significant better outcome, but at the same time, each therapy needs to be investigated for safety and efficacy.