Chinese medicine NeuroAiD efficacy stroke recovery-extension study (CHIMES-E study): an observational multicenter study to investigate the longer-term efficacy of NeuroAiD in stroke recovery.

BACKGROUND: Stroke carries a poor long-term prognosis for death and disability. There are few acute treatments that reduce death and disability after stroke. The ongoing international, multicenter, randomized, placebo-controlled, double-blind CHIMES trial is currently testing the hypothesis that a 3-month course of the traditional Chinese medicine MLC601 (NeuroAiD) is superior to placebo in reducing neurological deficit and improving functional outcome after acute ischemic stroke in patients receiving standard stroke care. This extension study tests the hypothesis that at 2 years, an initial 3-month administration of NeuroAiD is superior to placebo in reducing neurological deficit and improving functional outcome in patients with cerebral infarction of an intermediate range of severity. METHODS: Study subjects will be those who are already participants in CHIMES - aged above 21 years, had signs and symptoms of acute stroke, 6 ≤ NIHSS ≤ 14, neuroimaging consistent with ischemic stroke, and received study medication within 72 h of stroke onset. A subject will not be eligible for inclusion in CHIMES-E if they have withdrawn consent from all participation and follow-up for CHIMES. Subjects will be contacted at 6, 12, 18 and 24 months after CHIMES enrollment. After verbal consent is obtained, subjects will be assessed for functional state by the modified Rankin scale (mRS) and Barthel Index (BI), and a history of recurrent vascular events as well as medical events. The primary outcome measure will be the mRS at month 24. Secondary outcome measures will be mRS and BI at 6, 12 and 18 months, and BI at 24 months. Analysis will be based on the intention-to-treat principle. If the number of patients lost to follow-up is substantial, a sensitivity analysis based on the last observation carried forward method will be carried out, to compare the results with those from the main analysis without imputation. Based on a cumulative odds ratio of 1.5 for the NeuroAiD group, a two-sided test of 5% type I error and an expected 30% dropout rate after 2 years of follow-up for the 1,100 patients recruited into CHIMES, the 770 subjects with mRS data expected to be available at year 2 yields an 89% power to detect a difference in efficacy between NeuroAiD and placebo. CONCLUSIONS: This study will provide evidence for the longer-term efficacy of an initial course of a neurorestorative therapy after acute ischemic stroke of intermediate severity.

CHIMES-I: sub-group analyzes of the effects of NeuroAiD according to baseline brain imaging characteristics among patients randomized in the CHIMES study.

RATIONALE: The clinical effects of neuroprotective and/or neurorestorative therapies may vary according to location and size of the ischemic injury. Imaging techniques can be useful in stratifying patients for trials that may be beneficial against particular ischemic lesion characteristics. AIM: To test the hypothesis that the efficacy of NeuroAiD compared with placebo in improving functional outcome and reducing neurological deficit in patients with cerebral infarction of intermediate severity varies between sub-groups of patients randomized in the main Chinese Medicine Neuroaid Efficacy on Stroke study when categorized according to baseline imaging characteristics. DESIGN: This is a retrospective cohort sub-group analysis of patients who participated in the main Chinese Medicine Neuroaid Efficacy on Stroke study, a multicenter, double-blind, placebo-controlled trial that recruited 1100 patients within 72 h of ischemic stroke onset with National Institutes of Health Stroke Scale 6-14 and were randomized to either NeuroAiD or placebo taken four capsules three times daily for three months. Review of the baseline images to classify the acute stroke lesions in terms of size, location, and extent of involvement will be performed retrospectively by two readers who will remain blinded as to treatment allocation and outcomes of the subjects. STUDY OUTCOMES: The primary efficacy end-point in the main Chinese Medicine Neuroaid Efficacy on Stroke study is the modified Rankin Scale grades at three-months. Secondary efficacy end-points are the National Institutes of Health Stroke Scale score at three-months; difference of National Institutes of Health Stroke Scale scores between baseline and 10 days and between baseline and three-months; difference of National Institutes of Health Stroke Scale sub-scores between baseline and 10 days and between baseline and three-months; modified Rankin Scale at 10 days, one-month, and three-months; Barthel index at three-months; and Mini Mental State Examination at 10 days and three-months. Analysis of these primary and secondary end-points will be performed for sub-groups defined in this study after review of the baseline brain imaging: nonlacunar and lacunar, cortical and sub-cortical, hemispheric vs. brainstem, Alberta Stroke Program Early CT score <7 and 7-10, and score <8 and 8-10.

Alternative therapies for stroke treatment in Asia.

Patients seek alternative therapies for stroke in Asia due to dissatisfaction with poststroke recovery. Most alternative therapies are of unproven benefit in rehabilitation. Well-conducted trials are needed to better define the role of alternative therapies in the process of poststroke recovery; the CHInese Medicine Neuroaid Efficacy on Stroke recovery is ongoing. However, further studies, better health education and rehabilitation services and centers are also required.

Safety profile of MLC601 (Neuroaid) in acute ischemic stroke patients: A Singaporean substudy of the Chinese medicine neuroaid efficacy on stroke recovery study.

BACKGROUND: Previous clinical trials have shown that Neuroaid (MLC601), a traditional Chinese medicine, shows good tolerability and superiority over another traditional Chinese medicine in terms of neurological disability and functional outcome and thus may be beneficial as part of a poststroke rehabilitation program. The safety of MLC601 on hemostasis, hematology and biochemistry has been established in normal subjects and patients with nonacute stroke over a short treatment period. We assessed the safety of Neuroaid in patients with acute stroke treated for 3 months in a substudy of an ongoing randomized placebo-controlled trial. METHODS: Laboratory tests (biochemical, hematological and electrocardiogram) were conducted at the month 3 follow-up, in addition to baseline tests. A total of 114 patients were recruited. As there were 13 dropouts, a total of 52 patients on MLC601 and 49 on placebo were available for analysis. Serious adverse events (SAEs) were also analyzed. RESULTS: There were no statistically or clinically significant differences between treatment groups in biochemical, hematological or electrocardiogram tests at month 3, nor any statistically or clinically significant differences in the absolute and relative changes of the various parameters between baseline and 3 months. SAEs were similar and were those commonly seen in stroke patients. CONCLUSIONS: Longer-term laboratory safety data show no differences between MLC601 and placebo, confirming the safety of MLC601 in acute stroke patients receiving a 3-month treatment.

A double-blind, placebo-controlled, randomized phase II pilot study to investigate the potential efficacy of the traditional chinese medicine Neuroaid (MLC 601) in enhancing recovery after stroke (TIERS).

BACKGROUND AND OBJECTIVE: Previous clinical studies have shown that Neuroaid (MLC 601) may be beneficial in post-stroke rehabilitation. Our aim was to investigate the efficacy of Neuroaid on motor recovery in ischemic stroke patients using rehabilitation endpoints in accordance with the International Conference on Harmonization/Good Clinical Practice guidelines, in order to provide predictive information for further larger trials. METHODS: This is a phase II double-blind, placebo-controlled pilot study of 40 subjects admitted with a recent (less than 1 month) ischemic stroke. All subjects were given either Neuroaid or placebo, 4 capsules 3 times a day for 4 weeks. Fugl-Meyer Assessment (FMA), National Institutes of Health Stroke Scale and Functional Independence Measure scores were measured at initiation of the treatment, and at 4 and 8 weeks. RESULTS: None of the outcomes was statistically significant between the two groups. However, FMA scores showed a positive trend for improvement with Neuroaid treatment over time. Subgroup analysis of subjects with posterior circulation infarction and severe stroke both showed a tendency for better recovery. CONCLUSION: Some positive trends were observed in the Neuroaid group. A larger multicenter trial focusing on severe stroke patients is needed to better evaluate the role of Neuroaid in aiding stroke recovery in rehabilitation.

Burden of stroke in Indonesia.

Stroke is the leading cause of death among Indonesians above five years of age, comprising 15.4% of all deaths, age-gender-standardised death rate 99/100 000, and age-gender-standardised disability-adjusted life years lost 685/100 000. Stroke prevalence is 0.0017% in rural Indonesia, 0.022% in urban Indonesia, 0.5% among urban Jakarta adults, and 0.8% overall. Frequent risk factors include hypertension, smoking and hypercholesterolaemia. The mean age of stroke patients is 58.8 years. Subarachnoid haemorrhage is found in 1.4% of patients, intracerebral haemorrhage in 18.5%, and ischaemic stroke in 42.9%. Only city hospitals have neurology, neurosurgery and neuroimaging services. Indonesia has 40 stroke units. Commonly used medications for stroke are easily available. Hospital-based rehabilitative services are available in large hospitals. Traditional medicine is widely practiced. Efforts to combat stroke include education, more stroke units and rehabilitative services especially in the rural areas.

A double-blind, placebo-controlled, randomized, multicenter study to investigate CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES Study).

UNLABELLED: Rationale Traditional Chinese Medications(TCM) have been reported to have beneficial effects in stroke patients, but were not rigorously evaluated by GCP standards. Aim This study tests the hypothesis that Neuroaid, a TCM widely used in China post-stroke, is superior to placebo in reducing neurological deficit and improving functional outcome in patients with acute cerebral infarction of an intermediate severity. Design This is a multicenter, randomised, double-blind, placebo-controlled study of Neuroaid in ischemic stroke patients with National Institute of Health Stroke Scale(NIHSS) 6-14 treated within 48 h of stroke onset. Neuroaid or placebo is taken (4 capsules) 3 times daily for 3 months. Treatments are assigned using block randomization, stratified for centers, via a central web-randomization system. With a power of 90% and two-sided test of 5% type I error, a sample size is 874. Allowing for a drop-out rate of up to 20%, 1100 individuals should be enrolled in this study. Study Outcomes The primary efficacy endpoint is the modified Rankin Scale(mRS) grades at 3 months. Secondary efficacy endpoints are the NIHSS score at 3 months; difference of NIHSS scores between baseline and 10 days, and between baseline and 3 months; difference of NIHSS sub-scores between baseline and 10 days, and between baseline and 3 months; mRS at 10 days, 1 month, and 3 months; Barthel index at 3 months; Mini Mental State Examination at 10 days and 3 months. Safety outcomes include complete blood count, renal and liver panels, and electrocardiogram. STUDY REGISTRATION: ClinicalTrials.gov identifier: NCT00554723.

Danqi Piantang Jiaonang (DJ), a traditional Chinese medicine, in poststroke recovery.

BACKGROUND AND PURPOSE: Stroke is a leading cause of death and disability worldwide. Despite improvements in acute stroke treatment, many patients only make a partial or poor recovery. Therefore, there is a need for treatments that would further improve outcome. Danqi Piantang Jiaonang (DJ; NeuroAid), a traditional Chinese medicine widely used in China to improve recovery after stroke, has been compared with another traditional Chinese medicine in 2 unpublished randomized clinical trials. The results of these studies were pooled and reanalyzed to assess efficacy and safety. METHODS: Six hundred five subjects were randomized in 2 randomized double-blinded, controlled trials to receive either DJ or Buchang Naoxintong Jiaonang. Subjects were treated for 1 month. Inclusion criteria were: (1) patients with recent (from 10 days to 6 months) ischemic stroke; (2) patients satisfying Western diagnostic standards for stroke and traditional Chinese medicine standards for diagnosis of apoplexy; and (3) Diagnostic Therapeutic Effects of Apoplexy score >/=10. RESULTS: The functional outcome, measured by the Comprehensive Function Score component of the Diagnostic Therapeutic Effects of Apoplexy scale, showed a statistically significant superiority of DJ over the control treatment group (relative risk, 2.4; 95% CI, 1.28 to 4.51; P=0.007). Tolerance was excellent in both groups. CONCLUSIONS: The pooled analysis of 2 unpublished trials of DJ, a traditional Chinese medicine currently approved in China to improve neurological recovery after stroke, shows good tolerability and superiority of DJ over another traditional Chinese medicine also approved for stroke. A large double-blind randomized clinical trial is required to further assess the safety and efficacy of DJ.

Danqi Piantan Jiaonang does not modify hemostasis, hematology, and biochemistry in normal subjects and stroke patients.

BACKGROUND AND OBJECTIVE: Previous studies on Danqi Piantan Jiaonang (DPJ, NeuroAid), a traditional Chinese medicine, in stroke patients showed promising results. Our aim was to determine the safety of DPJ in normal subjects and stroke patients through a series of studies assessing its immediate and long-term effects, alone and in combination with aspirin, on hematological, hemostatic, and biochemical parameters. METHODS: We conducted 3 studies from December 2004 to May 2006. Study 1 was a case series which recruited 32 healthy volunteers who were given 2 oral doses of 4 DPJ capsules (0.4 g/capsule) 6 h apart. Study 2 was a randomized controlled trial of 22 healthy volunteers who received either 1 oral dose of aspirin 300 mg alone or a combination of 1 dose of aspirin 300 mg and 2 doses of 4 DPJ capsules taken 6 h apart. For both studies 1 and 2, hemostatic parameters (prothrombin time, activated partial thromboplastin time, fibrinogen, platelet aggregation, D-dimer) were tested at baseline, and after 2 and 8 h. Study 3 was a case series which recruited 10 patients with recent ischemic stroke (within 7 days) who were given 4 DPJ capsules taken orally 3 times a day for 1 month. Blood tests for hemostatic, hematological (complete blood count), and biochemical parameters (glucose, creatinine, alanine aminotransferase, aspartate transaminase, C-reactive protein) were performed at baseline, and after 1 and 4 weeks. RESULTS: Apart from the expected changes in platelet aggregation in subjects taking aspirin, no significant differences were detected in hemostatic parameters at baseline, and 2 and 8 h after oral intake of DPJ alone or in combination with aspirin. Likewise, no significant differences were observed in hematological, hemostatic, and biochemical parameters at baseline, and after 1 and 4 weeks of oral intake of DPJ. CONCLUSION: DPJ does not significantly modify hematological, hemostatic, and biochemical parameters in normal subjects and stroke patients.

Stroke disease management--a framework for comprehensive stroke care.

Disease management is an approach to patient care that coordinates medical resources for the patient across the entire healthcare delivery system throughout the lifetime of the patient with the disease. Stroke is suitable for disease management as it is a well-known disease with a high prevalence, high cost, variable practice pattern, poor clinical outcome, and managed by a non-integrated healthcare system. It has measurable and actionable outcomes, with available local expertise and support of the Ministry of Health. Developing the programme requires a multidisciplinary team, baseline data on target populations and healthcare services, identification of core components, collaboration with key stakeholders, development of evidence-based clinical practice guidelines and carepaths, institution of care coordinators, use of information technology and continuous quality improvement to produce an effective plan. Core components include public education, risk factor screening and management, primary care and specialist clinics, acute stroke units, inpatient and outpatient rehabilitation facilities, and supportive community services including medical, nursing, therapy, home help and support groups for patients and carers. The family physician plays a key role. Coordination of services is best done by a network of hospital and community-based care managers, and is enhanced by a coordinating call centre. Continuous quality improvement is required, with audit of processes and outcomes, facilitated by a disease registry. Pitfalls include inappropriate exclusion of deserving patients, misuse, loss of physician and patient independence, over-estimation of benefits, and care fragmentation. Collaboration and cooperative among all parties will help ensure a successful and sustainable programme.

Stroke pathways.

Stroke pathways are task-orientated structured multidisciplinary care plans which detail essential steps and interventions during the period of care of a "typical" stroke patient. Pathway development and implementation are best achieved by an appointed champion leading a multidisciplinary team of health care workers and administrators, who will also be the end users of the pathway. Pathway development involves reviews of existing clinical practice guidelines and pathways, followed by documentation, interdigitation and prioritization of care requirements at different time points in the various spheres, taking into consideration local philosophies and practices. These spheres could include investigations, pharmacologic treatment, rehabilitative therapy, nursing measures, and patient education. This would result in evidence-based holistic quality care, wide support base, efficient service provision, reduced costs and length of stay, less practice variation, improved communication among disciplines, enhanced patient-staff relationship, ease of audit and research opportunities. Components of the pathway could include a patient summary sheet, multidisciplinary record of the various activities structured on a day-to-day basis, sign-off columns for staff responsible for performing those activity, variance sheet, and separate protocols for specific issues. Implementation requires training of users, pilot runs, feedback, regular revisions, monitoring of compliance, and analysis of variances. Widespread implementation of pathways may be hindered by lack of support, and concerns about increased time requirements and costs, stifling of innovation, restriction of application of clinical judgement, lack of applicability to all patients, misuse and legal issues. However, a well-designed pathway will ensure quality care in a cost-efficient manner, benefiting the patient, carer and the health care service.