The NICE study is a phase IV clinical designed as a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, which is being carried out in 23 centers in China (Additional file
: Appendix). The study design is presented in Figure
. The inclusion criteria and major exclusion criteria are shown as the following.
The NICE study flowchart. The intention-to-treat (ITT).
The inclusion criteria are:
Male or female, aged 30-80;
Acute ischemic stroke diagnosed according to ICD-10 and CT/MRI criteria;
≤7d after the stroke;
Dementia threshold corrected based on educational year (>17 scores, >20 scores and >24 scores for illiterate, primary school, and above middle school respectively);
MoCA <26 scores for >12 educational years (or <25 scores for ≤12 educational years);
Hachinski ≥7 scores;
Expected good compliance with the therapy and follow-up. Already obtained written informed consent form.
Major exclusion criteria are:
Pregnant or lactating women;
History of mental diseases (eg. Schizophrenia and serious anxiety depression);
Patients with AD, Parkinson's disease, frontotemporal dementia or Huntington's disease (including the existing dementia diagnosed before the stroke or the past definite cognitive impairment);
Dementia of other causes (eg. injury of central nervous system, tumor, infection, metabolic disease, hydrocephalus at normal pressure, deficiency of folic acid/vitamin B12 and hypothyroidism);
Patients with other influencing factors for cognition evaluation (eg. aphasia, serious auditory/visual impairment and hemiplegia at dominant side);
Patients with contraindications for dihydropyridines;
Patients with serious arrhythmia, heart rate
120 bpm (or
50 bpm); ever myocardial infarction within 6 months; BP
90/60 mmHg; serious heart failure (unable to engage in any physical activity, and dyspnea and cardiac edema or angina pectoris at rest);
Patients having serious kidney incompetence: Creatinine >1.5 times of upper limit of normal value (ULN);
Patients with serious liver incompetence: AST/ALT level >3 times of ULN;
History of known allergy;
History of blood coagulation dysfunction, hemorrhagic disease, thrombocytopenia, leukocytopenia or neutropenia, serious anemia, Hb
History of serious gastrointestinal disease;
Patients with any known malignant tumor;
Patients with epilepsy and/or ever having antiepileptic drugs.
The diagnosis of acute ischemic stroke is determined by clinical examination and magnetic resonance imaging (MRI). The threshold of MMSE scores is corrected based on years of education (>17 scores, >20 scores and >24 scores for illiterate, primary school, and above middle school respectively)
]. Montreal cognitive assessment (MoCA) scores are <26 for >12 educational years, and <25 for ≤12 educational years
]. Hachinski scores are
Ethics and informed consent
The study is being performed in accordance with the ethical principles proclaimed in the Declaration of Helsinki in 1964, and revised in Tokyo in 2004. The study protocol has been reviewed by independent ethics committees in China, and by coordinators, investigators, and sponsors in accordance with local regulations. According to local requirements, thorough study information is provided to patients and written informed consent is obtained from each patient or surrogate family member before inclusion in the study. The NICE study is registered with clinicaltrials.gov (registration number: NCT01220622).
Treatment and follow-up
Inclusion and exclusion criteria are verified and it is decided for each patient whether the study drug can be administered within 7
days after the onset of ischemic stroke. Patients are given nimodipine, 30
mg, tid, three tablets daily, or placebo, 30
mg, tid, three tablets daily. Intervention allocation is based on balanced, randomized, permuted blocks which were produced by a third party statistician who was blinded to the whole protocol. The study interventions are identical in appearance, and investigators and patients are blinded to intervention allocation. Aside from basic treatment for acute ischemic stroke, cholinesterase inhibitors, NMDA receptor antagonists, or drugs from the racetam family cannot be used in this study. The following information is collected at the baseline assessment:
(1) Demographic data;
(2) Blood pressure, temperature, and pulse rate;
(3) Time from stroke onset;
(4) Medical history;
(5) Previous and ongoing medications;
(6) Assessing vascular dementia according to National Institute of Neurological Disorders and Stroke, -and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) criteria;
(7) NIH stroke scale (NIHSS), ADAS-cog, Frontal assessment battery (FAB), Alberta stroke program early CT score (ASPECTS), Fazekas, The cholinergic pathways hyperintensities scale (CHIPS).
Follow-up visits are carried out at 1, 3, and 6
). A physical examination is performed, and concomitant treatments are recorded at every visit. Compliance is determined by counting tablets at every visit. Cognitive function is assessed using MMSE, MoCA, ADAS-cog, and FAB, at 3 and 6
Safety is evaluated at every visit, including adverse events (AE) and serious adverse events (SAE), regardless of whether they are related to the administration of the study drug or course of therapy. All AE or SAE are reported and followed up completely. Laboratory tests are collected at 3 and 6
months. Patients who break off study intervention and informally withdraw consent will be followed up for the duration of the study.
The primary efficacy is defined as the combined results of the following efficacy criteria:
(1) MMSE (0–30)
(2) ADAS-cog (0–70)
MMSE is widely used for assessing cognitive function
], and ADAS-cog also includes items used in evaluating cognitive function
]. These two criteria have high reliability, and have been used in other stroke trials
]; therefore the validation of the study results is possible.
The primary end-point for evaluating the efficacy of nimodipine for prevention/treatment of cognitive impairment is 6
months after acute ischemic stroke events.
The secondary study end-points include the following analysis:
(1) the efficacy criteria of MoCA (0–30) and FAB (0–18) at 3 and 6
(2) the efficacy criteria of MMSE and ADAS-cog at 3
(3) the individual items of ADAS-cog, MoCA and FAB at 3
(4) the individual items of ADAS-cog, MoCA and FAB at 6
(5) the time course of MMSE, ADAS-cog, MoCA and FAB;
(6) overall mortality.
In this multicenter trial, we plan to enroll approximately 656 patients, with approximately 328 patients per study group. Approximately 23 centers in China are participating, with each center enrolling about 30 patients. We assumed that there was no significant difference between nimodipine (90
mg/d) and placebo (90
mg/d) in the prevention/treatment of aggravated cognitive impairment of acute ischemic stroke in the 6
month follow-up. For a statistical power of at least 90% in this trial, we estimated that 656 patients are necessary to present the superiority of nimodipine versus placebo. This corresponds to a relative risk (RR) reduction of 22% (RR is 0.78 for the nimodipine group), using a two-sided test (α
0.05, allowing 5% dropout). The efficacy analysis is based on an intention-to-treat method. Missing values are still treated as missing. Patients are examined at the last follow-up (at the occurrence of clinical event, the end of study, or the last follow-up before drop-out). A Kaplan-Meier curve is used to simulate the cumulative risk for cognitive impairment in the follow-up at day 180. The Cox proportional hazard model is used to calculate hazard proportion and 95% confidence interval. Log-rank test is used to evaluate the efficacy.
Most secondary outcome analyses will adopt the strategy of the primary outcome analyses. Continuous variables (for example MoCA and FAB) will undergo multi-variate linear regression analysis. Converted and/or weighted least square methods are regarded as abnormal and heterogeneous variance of remedial measures. Limit values will undergo a validity test. The conclusion will undergo sensitivity analysis.
The NICE trial is headed by a steering committee (Additional file
: Appendix), which is assisted by an independent data safety and monitoring board (DSMB). Trial monitoring and data management is performed by Giant Med-Pharma Service Group. The Steering Committee will regularly review the status of the trial and available blinded data, and will perform appropriate actions according to the conduct of the study. A face-to-face Executive Committee meeting will be required to make major decisions. To ensure the study meets the highest standards of ethics and patient safety, the Safety and Monitoring Board will meet regularly and monitor the progress of the study. The Board is composed of Academic Members, including an independent statistician, who are not otherwise participating in the trial. Clinical end-point events (stroke, myocardial infarction, death, and overt bleedings) will be reviewed by independent experts (neurologists, cardiologists) in the Critical Events Committee. The sponsor of the NICE trial is the Minister of Science and Technology of the People's Republic of China. The sponsor has no influence on the study design, data collection, data analysis, and final drafting of this manuscript.