Association between Baseline NIHSS Limb Motor Score and Functional Recovery after Stroke: Analysis Based on a Multicountry Dataset.

INTRODUCTION: Motor skills are the domains most often affected by stroke, but a comprehensive assessment of motor function is often impractical in the acute setting. It could be useful to have a brief simple tool allowing the stratification of patients at the time of inclusion in clinical studies. Hence, our primary objective was to evaluate whether the baseline NIH Stroke Scale limb motor score (b-NIHSS-LMS), obtained by summing the four motor items 5a to 6b of the NIHSS, is associated with functional recovery assessed by the modified Rankin Score (mRS). A secondary objective was to apply this new tool in the context of a clinical trial. METHODS: The analysed population considered for this research included subjects from a large published, double-blind, multicentre trial, randomised to receive either a combination of various herbal and non-herbal components (MLC601) or placebo, administered within 72 h after an acute ischaemic stroke of intermediate severity (defined by baseline NIH Stroke Scale [b-NIHSS] score of 8-14). Associations between b-NIHSS-LMS and favourable outcome, i.e., mRS 0-1 at month 3, were evaluated using logistic regression adjusted for baseline covariates and study treatment. RESULTS: The analysis included 533 subjects with an acute ischaemic stroke of intermediate severity assessed at month 3. Analyses showed that b-NIHSS-LMS was independently associated with a favourable outcome (OR 0.84; 95% confidence interval 0.76-0.92; p < 0.0003) at 3 months. Furthermore, in the clinical study considered, a selection of patients based upon a sufficient level of motor impairment at study entry (b-NIHSS-LMS ≥3) would result in the detection of a more pronounced and longer-lasting treatment effect. Indeed, ORs of treatment effect versus placebo in the selected subgroup (b-NIHSS-LMS ≥3) were statistically significant from months 3-24. DISCUSSION/CONCLUSIONS: As an independent association between b-NIHSS-LMS and functional recovery after an acute ischaemic stroke of intermediate severity was established in this study, we suggest that the b-NIHSS-LMS can be used as a stratification factor in large clinical trials to define a target population with poststroke motor impairments.

Stroke Burden in Malaysia.

Malaysia is located in the heart of South East Asia with two land masses, Peninsular Malaysia and East Malaysia which are separated by the South China Sea. Stroke or cerebrovascular disease is Malaysia's third leading cause of death. There were 47, 911 incident cases, 19,928 deaths, 443,995 prevalent cases, and 512,726 DALYs lost due to stroke in 2019. Successive national health and morbidity surveys from 2006 demonstrated a continuous rise in the prevalence of risk factors such as diabetes, hyperlipidaemia, and obesity. These risk factors are implicated in an increase in stroke incidence in those under 65 years of age, the largest increase of 53.3% and 50.4% in men and women, respectively, from the age strata of 35-39 years. The neurologist-to-patient ratio is 1:323,000 with the majority of neurologists working in urban centres. The healthcare system is provided predominantly by the public and private sectors. Concurrent use of traditional and complementary medicine is common and widely accepted. Challenges include delivering adequate care to rural communities, the low overall ischaemic stroke thrombolysis rates, and the high cost of thrombectomy devices for use in large vessel occlusions which have to be borne out-of-pocket by patients and their families. Effort is required to continue improving stroke care services in parallel with primary and secondary prevention strategies in the future, given the ageing population and the rising number of strokes in young adults nationally. Strategies include careful planning, inter-hospital cooperation, and increased allocation of resources from the government.

Alzheimer's Disease THErapy With NEuroaid (ATHENE): A Randomized Double-Blind Delayed-Start Trial.

OBJECTIVES: Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression. DESIGN: Randomized double-blind placebo-controlled delayed-start study. SETTING AND PARTICIPANT: Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n = 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6 months, followed by a further 6 months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035). METHODS: The primary outcome measure was occurrence of serious adverse events (SAEs) at 6 months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales. RESULTS: There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference -4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD) -1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences. CONCLUSIONS AND IMPLICATIONS: This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD.

Interactions of comorbid neuropsychiatric subsyndromes with neurodegenerative and cerebrovascular pathologies on cognition.

Comorbid neuropsychiatric symptoms are commonly found in individuals with dementia and is likely influenced by a combination of neurodegenerative and cerebrovascular pathophysiology. We evaluated the associations of a validated composite MRI-based quantitative measure of both neurodegeneration (hippocampus volume and cortical thickness of AD-specific regions) and cerebrovascular disease (CeVD; white matter hyperintensities and infarcts) with neuropsychiatric subsyndromes, and their interactions on cognition in a community-based sample across the disease spectrum (N = 773). Lower composite MRI scores corresponding to greater comorbid neurodegeneration and CeVD burden were associated with hyperactivity (OR = 1.48) and apathy (OR = 1.90) subsyndromes. Lower MRI scores with concomitant hyperactivity was associated with greater cognitive impairment, especially in patients who were at least moderately impaired, while the interaction with apathy was not dependent on disease stage. These MRI scores interaction models resulted in a better fit than models consisting of neurodegeneration or CeVD alone. Integrating multiple biomarkers with specific, disease stage-dependent neuropsychiatric subsyndromes may provide a more holistic risk profile to facilitate the identification of individuals at the highest risk of disease progression.

Burden of Stroke in Myanmar.

Myanmar is home to over 51 million people. The age- and sex-standardized mortality rate due to stroke is 165.4/100,000, while the rate of age- and sex-standardized disability-adjusted life years lost due to stroke is 2971.3/100,000. The prevalence of stroke among adults aged 40-99 years is 1.5%. Stroke is the leading cause of morbidity and mortality and comprises 20% of the neurological workload. There are only 10 stroke units in the whole country. Doctors are aware of the importance of hypertension in stroke prevention and the need for physiotherapy after stroke, but, until recently and in rural areas, they also tend to use steroids and neuroprotectants, and lower blood pressure aggressively acutely after stroke; antiplatelets are not widely used. Thrombolysis service is available at some tertiary centers but mechanical thrombectomy is not yet available.

Complementary and alternative interventions for stroke recovery - a narrative overview of the published evidence.

OBJECTIVES: Stroke survivors dissatisfied with their progress often seek complementary and alternative interventions (CAI). This paper reviews the evidence for CAIs in stroke recovery. METHODS: A literature search was performed for publications until December 2019 of CAI for stroke in Pubmed, Cochrane Library, EMBASE, CINAHL, AMED. Evidence was assessed according to Oxford Centre for Evidence-based Medicine criteria. RESULTS: In a meta-analysis, acupuncture reduced death or dependency compared to control at the end of follow-up and over the long term (≥3 months), OR 0.61(95%CI 0.46-0.79) and OR 0.67(95%CI 0.53-0.85) respectively, but was neutral against sham acupuncture. A Cochrane review of acupuncture vs. sham acupuncture in subacute or chronic stroke vs. showed no differences in motor function and quality of life. Three trials found favourable effects of moxibustion on motor function (SMD=0.72, 95%CI 0.37-1.08, p<0.0001). Two trials showed cupping compared to acupuncture reduced hemiplegic shoulder pain and upper-limb 'myodynamia'. A meta-analysis of traditional Chinese medicines for ischaemic stroke showed marked improvement in neurological deficit on stroke scales. There was no evidence for Ayurveda, homoeopathy or reiki. Tui-na reduced the Modified Ashworth Scale in some muscle groups. Marma massage improved Motricity Index and trunk control. Thai massage and herbal treatments improved the Barthel Index. On meta-analysis, Yoga improved memory and anxiety, while tai-chi improved activities of daily living, balance and walking ability. Studies were generally of poor quality. CONCLUSIONS: The evidence for benefit of CAIs for stroke recovery is weak. More research is needed to justify these treatments for stroke, by well-conducted, adequately-sized, double-blinded, randomized controlled trials.

Strategies for the use of Ginkgo biloba extract, EGb 761® , in the treatment and management of mild cognitive impairment in Asia: Expert consensus.

BACKGROUND: Mild cognitive impairment (MCI) is a neurocognitive state between normal cognitive aging and dementia, with evidence of neuropsychological changes but insufficient functional decline to warrant a diagnosis of dementia. Individuals with MCI are at increased risk for progression to dementia; and an appreciable proportion display neuropsychiatric symptoms (NPS), also a known risk factor for dementia. Cerebrovascular disease (CVD) is thought to be an underdiagnosed contributor to MCI/dementia. The Ginkgo biloba extract, EGb 761® , is increasingly being used for the symptomatic treatment of cognitive disorders with/without CVD, due to its known neuroprotective effects and cerebrovascular benefits. AIMS: To present consensus opinion from the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) regarding the role of EGb 761® in MCI. MATERIALS & METHODS: The ASCEND Group reconvened in September 2019 to present and critically assess the current evidence on the general management of MCI, including the efficacy and safety of EGb 761® as a treatment option. RESULTS: EGb 761® has demonstrated symptomatic improvement in at least four randomized trials, in terms of cognitive performance, memory, recall and recognition, attention and concentration, anxiety, and NPS. There is also evidence that EGb 761® may help delay progression from MCI to dementia in some individuals. DISCUSSION: EGb 761® is currently recommended in multiple guidelines for the symptomatic treatment of MCI. Due to its beneficial effects on cerebrovascular blood flow, it is reasonable to expect that EGb 761® may benefit MCI patients with underlying CVD. CONCLUSION: As an expert group, we suggest it is clinically appropriate to incorporate EGb 761® as part of the multidomain intervention for MCI.

Frequency and Clinical Impact of Serious Adverse Events on Post-Stroke Recovery with NeuroAiD (MLC601) versus Placebo: The CHInese Medicine Neuroaid Efficacy on Stroke Recovery Study.

BACKGROUND: Most comparative clinical trials are designed to assess the treatment effect for efficacy endpoints, with less emphasis on the analysis of safety outcomes. However, an extensive analysis of safety data could demonstrate beneficial results in terms of effectiveness by reducing serious adverse events (SAEs), and their unfavourable clinical impact on the study population. We aimed to conduct an exploratory analysis of the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study safety database comparing the frequency of SAEs and their clinical impacts among subjects having received MLC601 or placebo during the first 3 months post-stroke. METHODS: Analyses were performed by using the safety database of the multicentre, randomised, double-blind, placebo-controlled CHIMES study of 3 months of NeuroAiD versus placebo in subjects with acute ischaemic stroke of intermediate severity in the preceding 72 h. SAEs as reported by investigators at any time-point during the 3-month study were analysed on their frequency and that of any of their outcomes (death, and life threatening, new and/or prolonged hospitalisation, disability, and medical importance, in surviving subjects), as well as their time to onset and resolution. RESULTS: Of the 1,099 subjects in the CHIMES study, 1,087 were included in the safety analysis (MLC601 = 542) and (placebo = 545); the 12 who did not receive study treatment were excluded. There was a total of 135 subjects with SAEs (MLC601 = 60, placebo = 75). At baseline, overall, subjects with SAEs were older and had lower MMSE score. In the MLC601 group, they had higher NIHSS score, and more frequently a history of ischaemic heart disease and hyperlipidaemia. The number of SAEs per subjects was statistically significantly lower in the MLC601 group than placebo one, especially for subjects with ≥2 SAEs (6.7 vs. 29.3%; p < 0.001). This benefit was seen throughout the study period and during the initial hospitalisation. The main clinical impact of SAEs was an increase in hospitalisation time, reduced in the MLC601 arm with the rate of subjects hospitalised for a prolonged period being significantly threefold lower in surviving subjects (1.1 vs. 3.7%; p < 0.01). CONCLUSIONS: This post hoc analysis of SAEs from the CHIMES study database shows that subjects receiving a 3-month course of MLC601 experienced fewer SAEs, with lower rates of harmful clinical impacts, especially in terms of hospitalisation duration. These findings could translate to a benefit in terms of reduction of both healthcare burden and additional medical costs.

NeuroAid II (MLC901) in Haemorrhagic Stroke.

Stroke is a leading cause of death and disability. NeuroAid (MLC601), which originates from Traditional Chinese Medicine, comprises herbal and animal components, and has been shown to improve the functional status of patients after ischaemic stroke. The use of NeuroAid II (MLC901), which comprises only the herbal components of MLC601, in haemorrhagic stroke has not been previously reported. Our patient is a 63-year-old male with a significant stroke risk factor of hypertension. He developed visual field defect, aphasia, unilateral weakness, and hemisensory loss. CT scan showed a left thalamic haemorrhage. In addition to anti-hypertensive therapy and intensive rehabilitation, he was prescribed MLC901. Over a period of 6 months, he had significant improvements in his motor, sensory, and speech function. There were no adverse events, serial brain CT scans showed resolution of the haemorrhage. MLC901 may have a role in post-stroke recovery after intracranial haemorrhage.

The Alzheimer's disease THErapy with NEuroaid (ATHENE) study protocol: Assessing the safety and efficacy of Neuroaid II (MLC901) in patients with mild-to-moderate Alzheimer's disease stable on cholinesterase inhibitors or memantine-A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Dementia is a large and growing health care burden globally, and its major cause is Alzheimer's disease (AD). MLC901 (Neuroaid II) is a simplified form of MLC601 (Neuroaid), a Traditional Chinese Medicine with neuroprotective and neuroproliferative properties in cellular and animal models of brain injury. MLC601 has been shown to modulate amyloid precursor protein (APP) processing in human neuroblastoma cell cultures and increase the levels of soluble APPα. In addition, MLC901 has been shown to reduce tau phosphorylation in vitro. Hence, MLC901 may have possible multimodal actions and a disease-modifying effect in AD. In previous clinical studies, MLC601 has shown promising effects in AD. OBJECTIVE: To investigate the safety and efficacy of MLC901 add-on therapy to standard treatment in mild-to-moderate probable AD patients stable on standard treatment and to evaluate if MLC901 has a disease-modifying effect in AD. METHODS: This is a 6-month randomized, double-blind, placebo-controlled trial in mild-to-moderate probable AD where MLC901 will be given as an add-on therapy to standard AD treatment, followed by an extension study for another 6 months, where all subjects will be treated with open-label MLC901 in addition to standard treatment. The primary outcome is safety as measured by adverse events, vital signs, electrocardiogram, laboratory tests, and physical and neurological examinations. Secondary outcomes evaluating cognition, behavior, and activities of daily living at various time points include the Alzheimer's Disease Assessment Scale-cognitive subscale, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Mini-Mental State Examination. CONCLUSION: MLC901 has the potential to improve cognition in AD patients. It may also have a role in delaying disease progression. This study will be the first to provide safety and efficacy data for MLC901 in mild-to-moderate probable AD patients already receiving standard therapy.

Haemoglobin, magnetic resonance imaging markers and cognition: a subsample of population-based study.

BACKGROUND: Low haemoglobin is highly prevalent among the elderly and has been associated with dementia. However, the mechanisms underlying this association with cognitive dysfunction, either through cerebrovascular disease or neurodegeneration, remain poorly understood. We aimed to examine the association of decreased haemoglobin levels with markers of cerebral small vessel disease (CSVD), neurodegeneration and cognitive impairment in an elderly Asian population. METHODS: A total of 796 Chinese, Malay and Indian participants aged 60 years and older from the Epidemiology of Dementia in Singapore study were included in this study. After providing information on demographics, anthropometry and cardiovascular risk factors, participants underwent 3-T brain magnetic resonance imaging (MRI) to measure markers of CSVD, including cerebral microbleeds, cortical cerebral microinfarcts, lacunes, enlarged perivascular spaces and white matter hyperintensities, as well as neurodegenerative markers, including cortical thickness and subcortical structure volumes quantified using FreeSurfer. Cognition was assessed using a detailed neuropsychological assessment. Logistic and linear regression models were constructed, adjusting for age, gender, education, race, body mass index, smoking, hypertension, hyperlipidaemia, diabetes, glomerular filtration rate and other MRI markers, to test the association between haemoglobin levels and the MRI markers and cognition. RESULTS: Decreased haemoglobin levels were associated with cerebral microbleeds, specifically lobar microbleeds (OR, 1.21; 95% CI, 1.04-1.40; p = 0.015). Decreased haemoglobin levels were also associated with occipital cortical thinning (mean difference, - 0.011; 95% CI, - 0.019, - 0.004; p = 0.003) and smaller accumbens volume (mean difference, - 0.01; 95% CI, - 0.02, 0.00; p = 0.005). A significant association was also observed between decreased haemoglobin levels and poorer global cognitive performance (mean difference, - 0.04; 95% CI, - 0.09, 0.00; p = 0.048). In cognitive domain analysis, associations were again observed between decreased haemoglobin levels and worse performance on attention (mean difference, - 0.05; 95% CI, - 0.10, - 0.01; p = 0.028) and language (mean difference, - 0.06; 95% CI, - 0.12, 0.00; p = 0.048) domains; however, these associations did not survive multiple comparison. CONCLUSIONS: Decreased haemoglobin levels were associated with lobar microbleeds, neurodegenerative markers and cognitive dysfunction. Future studies should ascertain whether iron, folate or vitamin B12 supplementation is able to ameliorate the onset and progression of cognitive impairment and dementia associated with low haemoglobin.

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

BACKGROUND AND PURPOSE: MLC601 has been shown in preclinical studies to enhance neurorestorative mechanisms after stroke. The aim of this post hoc analysis was to assess whether combining MLC601 and rehabilitation has an effect on improving functional outcomes after stroke. METHODS: Data from the CHInese Medicine NeuroAiD Efficacy on Stroke (CHIMES) and CHIMES-Extension (CHIMES-E) studies were analyzed. CHIMES-E was a 24-month follow-up study of subjects included in CHIMES, a multi-centre, double-blind placebo-controlled trial which randomized subjects with acute ischemic stroke, to either MLC601 or placebo for 3 months in addition to standard stroke treatment and rehabilitation. Subjects were stratified according to whether they received or did not receive persistent rehabilitation up to month (M)3 (non- randomized allocation) and by treatment group. The modified Rankin Scale (mRS) and Barthel Index were assessed at month (M) 3, M6, M12, M18, and M24. RESULTS: Of 880 subjects in CHIMES-E, data on rehabilitation at M3 were available in 807 (91.7%, mean age 61.8 ± 11.3 years, 36% female). After adjusting for prognostic factors of poor outcome (age, sex, pre-stroke mRS, baseline National Institute of Health Stroke Scale, and stroke onset-to-study-treatment time), subjects who received persistent rehabilitation showed consistently higher treatment effect in favor of MLC601 for all time points on mRS 0-1 dichotomy analysis (ORs 1.85 at M3, 2.18 at M6, 2.42 at M12, 1.94 at M18, 1.87 at M24), mRS ordinal analysis (ORs 1.37 at M3, 1.40 at M6, 1.53 at M12, 1.50 at M18, 1.38 at M24), and BI ≥95 dichotomy analysis (ORs 1.39 at M3, 1.95 at M6, 1.56 at M12, 1.56 at M18, 1.46 at M24) compared to those who did not receive persistent rehabilitation. CONCLUSIONS: More subjects on MLC601 improved to functional independence compared to placebo among subjects receiving persistent rehabilitation up to M3. The larger treatment effect of MLC601 was sustained over 2 years which supports the hypothesis that MLC601 combined with rehabilitation might have beneficial and sustained effects on neuro-repair processes after stroke. There is a need for more data on the effect of combining rehabilitation programs with stroke recovery treatments.

Durability of the beneficial effect of MLC601 (NeuroAiD™) on functional recovery among stroke patients from the Philippines in the CHIMES and CHIMES-E studies.

Background and Aim A pre-specified country analysis of subjects from the Philippines in the CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) Study showed significantly improved functional and neurological outcomes on MLC601 at month (M) 3. We aimed to assess these effects on long-term functional recovery in the Filipino cohort. Methods The CHIMES-E (extension) Study evaluated subjects who completed three months of randomized placebo-controlled treatment in CHIMES up to two years. Blinding of treatment allocation was maintained and all subjects received standard stroke care and rehabilitation. Modified Rankin Score (mRS) and Barthel Index (BI) were assessed in-person at M3 and by telephone at M6, M12, M18, M24. Odds ratios (OR) with corresponding 95% confidence intervals (CI) for functional recovery using ordinal analysis of mRS and for achieving functional independence (mRS 0-1 or BI ≥ 95) at each time point were calculated, adjusting for age, sex, baseline National Institute of Health Stroke Scale (NIHSS), onset-to-treatment time (OTT) and pre-stroke mRS. Results The 378 subjects (MLC601 192, placebo 186) included in CHIMES-E from the Philippines (mean age 60.2 ± 11.1) had more women ( p < 0.001), worse baseline NIHSS ( p < 0.001) and longer onset to treatment time ( p = 0.002) compared to other countries. Baseline characteristics were similar between treatment groups. The treatment effect of MLC601 seen at M3 peaked at M6 with OR for mRS shift of 1.53 (95% CI 1.05-2.22), mRS dichotomy 0-1 of 1.77 (95% CI 1.10-2.83), and BI ≥ 95 of 1.87 (95% CI 1.16-3.02). The beneficial effect persisted up to M24. Conclusion The beneficial effect of MLC601 seen at M3 in the Filipino cohort is durable up to two years after stroke.

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

BACKGROUND: The Chinese Medicine NeuroAiD Efficacy on Stroke recovery - Extension (CHIMES-E) study is among the few acute stroke trials with long-term outcome data. We aimed to evaluate the recovery pattern and the influence of prognostic factors on treatment effect of MLC601 over 2 years. METHODS: The CHIMES-E study evaluated the 2 years outcome of subjects aged ≥18 years with acute ischemic stroke, National Institutes of Health Stroke Scale (NIHSS) score 6-14, pre-stroke modified Rankin Scale (mRS) score ≤1 included in a multicenter, randomized, double-blind, placebo-controlled trial of MLC601 for 3 months. Standard stroke care and rehabilitation were allowed during follow-up with mRS score being assessed in-person at month (M) 3 and by telephone at M1, M6, M12, M18 and M24. RESULTS: Data from 880 subjects were analyzed. There was no difference in baseline characteristics between treatment groups. The proportion of subjects with mRS score 0-1 increased over time in favor of MLC601 most notably from M3 to M6, thereafter remaining stable up to M24, while the proportion deteriorating to mRS score ≥2 remained low at all time points. Older age (p < 0.01), female sex (p = 0.06), higher baseline NIHSS score (p < 0.01) and longer onset to treatment time (OTT; p < 0.01) were found to be predictors of poorer outcome at M3. Greater treatment effect, with more subjects improving on MLC601 than placebo, was seen among subjects with 2 or more prognostic factors (OR 1.65 at M3, 1.78 at M6, 1.90 at M12, 1.65 at M18, 1.39 at M24), especially in subjects with more severe stroke or longer OTT. CONCLUSIONS: The sustained benefits of MLC601 over 2 years were due to more subjects improving to functional independence at M6 and beyond compared to placebo. Selection of subjects with poorer prognosis, particularly those with more severe NIHSS score and longer OTT delay, as well as a long follow-up period, may improve the power of future trials investigating the treatment effect of neuroprotective or neurorestorative therapies.

Sex and the treatment effect in the Chinese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) trial.

In the randomized controlled trial of NeuroAiD versus placebo following ischemic stroke, there was a trend for sex influencing the treatment effect of NeuroAiD in improving functional outcome following ischemic stroke (p=0.075).

The NeuroAiD Safe Treatment (NeST) Registry: a protocol.

INTRODUCTION: NeuroAiD (MLC601, MLC901), a combination of natural products, has been shown to be safe and to aid neurological recovery after brain injuries. The NeuroAiD Safe Treatment (NeST) Registry aims to assess its use and safety in the real-world setting. METHODS AND ANALYSIS: The NeST Registry is designed as a product registry that would provide information on the use and safety of NeuroAiD in clinical practice. An online NeST Registry was set up to allow easy entry and retrieval of essential information including demographics, medical conditions, clinical assessments of neurological, functional and cognitive state, compliance, concomitant medications, and side effects, if any, among patients on NeuroAiD. Patients who are taking or have been prescribed NeuroAiD may be included. Participation is voluntary. Data collected are similar to information obtained during standard care and are prospectively entered by the participating physicians at baseline (before initialisation of NeuroAiD) and during subsequent visits. The primary outcome assessed is safety (ie, non-serious and serious adverse event), while compliance and neurological status over time are secondary outcomes. The in-person follow-up assessments are timed with clinical appointments. Anonymised data will be extracted and collectively analysed. Initial target sample size for the registry is 2000. Analysis will be performed after every 500 participants entered with completed follow-up information. ETHICS AND DISSEMINATION: Doctors who prescribe NeuroAiD will be introduced to the registry by local partners. The central coordinator of the registry will discuss the protocol and requirements for implementation with doctors who show interest. Currently, the registry has been approved by the Ethics Committees of Universiti Kebangsaan Malaysia (Malaysia) and National Brain Center (Indonesia). In addition, for other countries, Ethics Committee approval will be obtained in accordance with local requirements. TRIAL REGISTRATION NUMBER: NCT02536079.

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

OBJECTIVE: The 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. METHODS: Analyses 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. RESULTS: Placebo 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.

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

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 treatment effect in the CHIMES study.

BACKGROUND: Stroke trials often analyze patients with heterogeneous prognoses using a single definition of outcome, which may not be applicable to all subgroups. We aimed to evaluate the treatment effects of MCL601 among patients stratified by prognosis in the Chinese Medicine Neuroaid Efficacy on Stroke Recovery (CHIMES) study. METHODS: Analyses were performed using data from the CHIMES study, an international, randomized, placebo-controlled, double-blind trial comparing MLC601 with placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. All subjects with baseline data and the modified Rankin Scale (mRS) score at 3 months were included. RESULTS: Data from 1006 subjects were analyzed. The predictive variables for mRS score greater than 1 at month 3 were age older than 60 years (P < .001), baseline National Institutes of Health Stroke Scale score 10-14 (P < .001), stroke onset to initiation of study treatment of more than 48 hours (P < .001), and female sex (P = .026). A higher number of predictors was associated with poorer mRS score at month 3 for both placebo (P < .001) and treatment (P < .001) groups. The odds ratio (OR) for achieving a good outcome increased with the number of predictors and reached statistical significance in favor of MLC601 among patients with 2 to 4 predictors combined (unadjusted OR = 1.44, 95% confidence interval, 1.02-2.03; adjusted OR = 1.60, 95% confidence interval, 1.10-2.34). CONCLUSIONS: Age, sex, baseline National Institutes of Health Stroke Scale score, and time to first dose are predictors of functional outcome in the CHIMES study. Stratification by prognosis showed that patients with 2 or more predictors of poorer outcome have better treatment effect with MLC601 than patients with single or no prognostic factor. These results have implications on designing future stroke trials.