CHInese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study (CHIMES-E): A Multicenter Study of Long-Term Efficacy

Abstract

Background: The CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) study was an international randomized double-blind placebo-controlled trial of MLC601 (NeuroAiD) in subjects with cerebral infarction of intermediate severity within 72 h. CHIMES-E (Extension) aimed at evaluating the effects of the initial 3-month treatment with MLC601 on long-term outcome for up to 2 years. Methods: All subjects randomized in CHIMES were eligible for CHIMES-E. Inclusion criteria for CHIMES were age ≥18, baseline National Institute of Health Stroke Scale of 6-14, and pre-stroke modified Rankin Scale (mRS) ≤1. Initial CHIMES treatment allocation blinding was maintained, although no further study treatment was provided in CHIMES-E. Subjects received standard care and rehabilitation as prescribed by the treating physician. mRS, Barthel Index (BI), and occurrence of medical events were ascertained at months 6, 12, 18, and 24. The primary outcome was mRS at 24 months. Secondary outcomes were mRS and BI at other time points. Results: CHIMES-E included 880 subjects (mean age 61.8 ± 11.3; 36% women). Adjusted OR for mRS ordinal analysis was 1.08 (95% CI 0.85-1.37, p = 0.543) and mRS dichotomy ≤1 was 1.29 (95% CI 0.96-1.74, p = 0.093) at 24 months. However, the treatment effect was significantly in favor of MLC601 for mRS dichotomy ≤1 at 6 months (OR 1.49, 95% CI 1.11-2.01, p = 0.008), 12 months (OR 1.41, 95% CI 1.05-1.90, p = 0.023), and 18 months (OR 1.36, 95% CI 1.01-1.83, p = 0.045), and for BI dichotomy ≥95 at 6 months (OR 1.55, 95% CI 1.14-2.10, p = 0.005) but not at other time points. Subgroup analyses showed no treatment heterogeneity. Rates of death and occurrence of vascular and other medical events were similar between groups. Conclusions: While the benefits of a 3-month treatment with MLC601 did not reach statistical significance for the primary endpoint at 2 years, the odds of functional independence defined as mRS ≤1 was significantly increased at 6 months and persisted up to 18 months after a stroke.

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

“…We have previously reported the overall benefit of MLC601 on functional independence at 6 months and beyond [6]. In this study, we demonstrate that the benefit was due to a larger proportion of subjects on MLC601 attaining functional independence by 6 months, thereafter maintaining their functional independence for up to 2 years, with fewer subjects deteriorating over time.…”

“…Baseline characteristics of subjects were similar between the treatment groups as previously described [6]. …”

“…Our study included subjects with stroke of mild to moderate severity with a median baseline NIHSS score of 8 (interquartile scores of 7 and 10) [6]. As can be seen in the placebo group, more than a quarter of the subjects recovered to an independent functional state at 1 month and more than 45% were independent at 3 months after a stroke.…”

“…CHIMES-E is a planned extension study to evaluate the long-term outcome of subjects included in CHIMES up to 2 years from stroke [6]. Treatment allocation blinding was maintained throughout the CHIMES-E study and all subjects received standard stroke care and appropriate rehabilitation as prescribed by the treating physician.…”

“…As neurorestorative processes require time, it is expected that clinical benefits would gradually accrue and appear only after a longer period of observation following treatment initiation. This hypothesis has recently been confirmed in the Chinese Medicine NeuroAiD Efficacy on Stroke recovery - Extension (CHIMES-E) study which showed that a 3-month treatment course of MLC601 after an acute ischemic stroke increased the odds of achieving functional independence at 6 months and beyond [6]. Recovery from stroke, however, is dynamic and deterioration may occur even after initial improvement [7].…”