The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD)

Abstract

ObjectiveThe CHIMES Study compared MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. We aimed to verify if patient selection based on two prognostic factors (ie, stroke severity and time to treatment) improves detection of a treatment effect with MLC601.MethodsAnalyses were performed using data from the CHIMES Study, an international, randomized, placebo‐controlled, double‐blind trial comparing MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. Three subgroups, that is, onset to treatment time (OTT) ≥48 hours; baseline National Institute of Health Stroke Scale (NIHSS) ≥10; both OTT ≥48 hours and baseline NIHSS ≥10, were analyzed using modified Rankin Scale (mRS) ≤1 and a composite endpoint of mRS ≤1, Barthel Index ≥95, and NIHSS ≤1 at month 3.ResultsPlacebo response rates were lower (ie, worse natural outcome) among subgroups with prognostic factors. Conversely, MLC601 treatment effects were significantly higher in the subgroups with prognostic factors than for the entire cohort, being highest among patients with both OTT ≥48 hours and baseline NIHSS of 10 to 14: odds ratios of 2.18 (95% CI 1.02 to 4.65) for month 3 mRS ≤1 and 3.88 (95% CI 1.03 to 14.71) for the composite endpoint.Conclusions: Patients who have moderately severe strokes and longer OTT demonstrate better treatment effects with MLC601. These factors can guide patient selection in future trials.

Prognostic Factors and Pattern of Long-Term Recovery with MLC601 (NeuroAiD™) in the Chinese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study

“…We recently showed that subjects with moderately severe stroke and/or longer stroke OTT improve the power of detecting differences in recovery between treatment groups at 3 months [9]. In this present analysis, NIHSS score and OTT individually improve the power even more after longer observations of up to 18 months, and NNT is low and stable over time, especially in subjects with more severe strokes.…”

“…We have identified several factors that predict poorer outcomes at 3 months, namely older age, female sex, worse baseline stroke severity and longer delay between stroke onset and initiation of treatment [6,8,9,10,15]. The same factors were reported in many in other previous studies [16,17,18,19,20,21,22] and were also found to predict deterioration at 1 and 5 years after a stroke [7,12,22,23,24].…”

“…It is thus important to understand the pattern of long-term recovery of subjects with stroke in a neurorestorative trial. In addition, we recently showed in the CHIMES study how predictors of functional outcome, such as age, sex, baseline National Institutes of Health Stroke Scale (NIHSS) score, and treatment delay, affect the ability of demonstrating treatment effect of a therapy for stroke recovery at 3 months [8,9]. …”

Therapeutic effect of Chinese herbal medicines for post stroke recovery

“…Traditional Chinese Medicine (TCM) has been historically used for stroke treatment, and is widely used today. [ 7 ] Chinese herbal medicine is an important component of TCM, which has several characteristics, including natural medicine, complex composition, and multifunction.…”

Effect of Combined Treatment with MLC601 (NeuroAiDTM) and Rehabilitation on Post-Stroke Recovery: The CHIMES and CHIMES-E Studies

“…The clinical evidence base for the efficacy and safety of MLC601 after acute ischemic stroke is provided by the large CHInese Medicine NeuroAiD Efficacy on Stroke Recovery (CHIMES; ClinicalTrials.gov: NCT00554723) and CHIMES-Extension (CHIMES-E) Studies [9,10]. In a post-hoc analysis, MLC601 showed a favorable effect on post-stroke recovery at 3 months in patients with persisting and/or moderately severe neurological deficit [11]. It also showed significant benefit (mRS < 1) at 6 months persisting up to 18 months [10], providing clinical evidence that supports the pre-clinical studies demonstrating neurorestorative effects.…”