The Cog-VACCINE Study: a Randomized Controlled Clinical Trial to Evaluate the Effect of Cognitive Training in Patients With Vascular Cognitive Impairment, no Dementia
Phase: NA
Conditions: Vascular Cognitive Impairment no Dementia
Sponsor: Beijing Friendship Hospital

Study Protocol and Statistical Analysis Plan 
 
Title: The efficacy of Cognitive training in patients with VAsCular Cognitive 
Impairment, No dEmentia (the Cog-VACCINE study): study protocol for a randomized 
controlled trial 
 
NCT number: 02640716 
 
Date of the document: 2015-03-13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Protocol 
 
Objective: Vascular cognitive impairment, no dementia (VCIND), which is also termed 
mild vascular cognitive disorder, refers to cognitive deficits associated with underlying 
vascular causes that fall short of a diagnosis of dementia. Although early intervention 
of VCIND holds the potential to delay or even reverse cognitive impairment, no 
treatment is available to prevent further decline in patients with VCIND. To date, no 
cognitive intervention study on VCIND has been published. Whether and how 
cognitive training improves cognitive function in patients with VCIND remains largely 
unknown. This trial is the first study to test the efficacy of cognitive training on VCIND 
using a double-blinded, randomized controlled trial design. To evaluate the efficacy of 
cognitive training, both traditional outcomes, such as neuropsychological assessment, 
and neuroplasticity outcomes, such as brain microstructure index, will be used. 
 
Design: This study will be implemented as a three-center double blinded randomized 
trial. The study was registered under clinicaltrials.gov (NCT02640716). This study will 
be reported in accordance with both the CONSORT statement and the CONSORT 
statement for non-pharmacological interventions. The primary objective is to assess 
whether cognitive training in patients with subcortical VCIND improves their cognitive 
abilities. The second objective is to evaluate the effect of cognitive training on neural 
plasticity. Finally, possible genetic and plasma biomarkers related to the effect of the 
training will be examined. 
 
Methods 
Participants 
Sixty patients with subcortical VCIND will be recruited on fulfillment of the inclusion 
criteria. The patients will be randomly allocated into the experimental group or the 
control group. Patients will be recruited in neurology clinics at Beijing Friendship 
Hospital, Xuan Wu Hospital, and the geriatric clinic at Fu Xing Hospital, Capital 
Medical University. 
 
Inclusion criteria 
1) Literate Han Chinese, aged 50 years or older, with a consistent caregiver who 
accompanies the subject at least 4 days per week. Patient or informant report of 
cognitive impairment involving memory or other cognitive domains lasting for at least 
3 months 
2) Neither normal nor demented according to the criteria of the Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition, with a Clinical Dementia 
Rating ≥0.5 on at least one domain and a global score ≤0.5; a Mini-Mental State 
Examination score ≥20 (primary school), or ≥24 (junior school or above). 
3) Normal or slightly impaired activities of daily living as defined by a total score of 
≤1.5 on the three functional Clinical Dementia Rating domains (home and hobbies, 
community affairs, and personal care).  
 

MRI entry criteria: 
1) At least three supratentorial subcortical small infarcts (3–20 mm in diameter), with 
or without white matter lesions of any degree; or moderate to severe white matter 
lesions (score ≥2 according to the Fazekas rating scale) with or without small infarcts 
2) Absence of cortical and watershed infarcts, hemorrhages, hydrocephalus, and white 
matter lesions with specific causes (e.g., multiple sclerosis) 
3) No hippocampal or entorhinal cortex atrophy (score 0 according to the medial 
temporal lobe atrophy scale of Scheltens). 
 
Exclusion criteria 
1) Severe aphasia, physical disabilities, or any other factor that might preclude 
completion of neuropsychological testing 
2) Clinically significant gastrointestinal, renal, hepatic, respiratory, infectious, 
endocrine, or cardiovascular system disease; cancer; alcoholism; drug addiction 
3) Disorders other than subcortical VCIND that might affect cognition; a Hamilton 
Depression Scale score >17 or schizophrenia; new strokes within 3 months before 
baseline; inherited or inflammatory small vessel disease 
4) Use of medications that may affect cognitive functioning, including tranquilizers, 
anti-anxiolytics, hypnotics, nootropics, and cholinomimetic agents; and inability to 
undergo brain MRI 
 
Randomization 
Participants will be randomly allocated to either the intervention group or the control 
group in a ratio of 1:1. After participants have given their informed consent, 
randomization will be performed by an independent statistician who is blinded to the 
patient interventions using simple randomization of random number table method in 
SAS software (SAS Institute, Inc., Cary, NC, USA). Afterwards, the sealed 
randomization codes and intervention number are sent out to each center. Blinding will 
be broken only if a participant needs emergency treatment. Once the blinding is broken, 
the participant will be managed as off-trial. 
 
Blinding 
Patients, caregivers, radiologists, statisticians, and neuropsychologists who measure the 
outcomes will be blinded to the randomization status. Blinding will also be maintained 
for data management, outcome assessment, and data analysis. 
 
Intervention 
Previous studies showed that training approaches with multi-domain, personalized, and 
adaptive training features are more effective. Therefore, cognitive training will be a 
computerized multi-domain adaptive training program in this trial. Training paradigms 
that were successfully used in previous studies will be adopted, including processing 
speed, attention, long-term memory, working memory, flexibility, calculation, and 
problem solving. Specific training paradigms include a time perception task, visual 
search task, rapid serial presentation task, delayed match to sample task, paired-

associate recall task, attention span task, digit span task, go–no go task, Stroop task, 
task switching, and n-back working memory task. To enable adaptive training, each task 
was designed with several difficulty levels. Based on previous tests with a large size 
sample, the tasks will be further grouped in each domain with varied task difficulty. At 
the beginning, assignment tasks from these domains will be similar across participants. 
On each training day, five tasks (2 min per task, each three times, in total 30 min per 
day) will be assigned. 
Within each task, high accuracy (>80 %) is required to upgrade. To manipulate the 
adaptive change, the number of types of stimuli, the presentation probability of each 
type of stimuli, and the size and duration of a stimulus were systematically set. To keep 
a systematical setting, only one parameter will be changed, while the other parameters 
will be kept as constant in one level upgraded. Once the task performance is higher than 
80 % of the norm performance of a normal aging population, the task will be replaced 
by a harder task from the same domain. The training is thus also adaptive at participant 
level, with a similar setup but personalized progress across participants.  
For the control group, processing speed and attention tasks are included, with five tasks 
and 30 min training in each day. Importantly, a fixed, primary difficulty level for all 
participants in the control group is set. The training will be completed at home and 
supervised by an independent neurologist over the internet (www.66nao.com). 
 
MRI data 
MRI data collection 
The MRI data were acquired on a 3·0T Siemens scanner. High-resolution T1-weighted 
images covering the whole brain were taken using a sagittal 3D magnetization prepared 
rapid gradient echo (MP-RAGE) sequence: repetition time (TR) = 1690 ms, echo time 
(TE) = 2·56 ms, slice thickness = 1 mm, flip angle = 12◦, field of view (FOV) = 256 × 
256 mm2. Rest-fMRI scan was acquired using multiband echo-planar imaging (EPI) 
sequence: TR = 2000 ms, TE =30 ms, 35 slices, voxel-size = 3·5 × 3·5 × 3·5 mm3, flip 
angle = 83◦, FOV = 224 × 224 mm2. DTI images were acquired by using a diffusion-
weighted double spin-echo EPI sequence: TR = 8000 ms, TE = 96 ms, 64 diffusion 
weighted directions with a b value of 1000 s/mm2 and 11 images with a b value of 0 
s/mm2, flip angle = 90◦, FOV = 224 × 224 mm2, in-plane resolution = 1·75 × 1·75 
mm2 voxels, 54 contiguous two-mm thick axial slices.  
 
Primary outcome measures 
The primary outcome measures are global cognitive function measured by the Montreal 
Cognitive Assessment (MoCA) and executive function measured by the Trail Making 
Test B-A (TMT B-A). 
 
Secondary outcome measures 
The secondary outcome measure is neuroplasticity changes, as measured by MRI. 
Specifically, the brain functional response, including regional activation magnitude and 
functional connectivity across regions will be assessed. For fMRI, both before and after 
the trial, a resting state scan, a scan with a cognitive control task, and a scan with an 

episodic memory task will be included. The brain response change during the tasks and 
functional connectivity across regions in the task and the resting state sessions will be 
examined between groups. The structural change, including gray matter volume, 
measured by voxel-based morphometrics, and white matter microstructure, measured 
by diffusion tensor imaging, will be assessed. 
 
Statistical Analyses 
In preliminary tests, the observed mean difference in change from baseline in the MoCA, 
Digit Span, WHO-UCLA Auditory Verbal Learning Test (WHO-UCLA AVLT), and 
Boston Naming Test (BNT) scores between training and control groups were 1·62, 
14·92, 3·35, and 7·59, respectively, and the standard deviations were1·93, 18·41, 4·05, 
and 9·06, respectively. According to these data, sample sizes of 44, 48, 46, and 46, 
respectively, were needed to obtain a statistical power of 80% with a significance level 
of 5%. We used the largest sample size of 48, and the inclusion number has been set to 
60 patients, allowing for a maximum dropout rate of 20%. In this study, a statistically 
significant difference (2-tailed p<0·05) on any of the two primary outcomes at the end 
of the intervention would be considered preliminary evidence of efficacy.    
Performance changes in the assessment scores related to global cognitive function 
(MoCA) and executive function (TMT B-A) are the primary outcome measures of 
interest. An independent sample t test will be used separately for the assessment 
criterion and the rating scales of function, to ensure that baseline levels are comparable 
between the training and control groups. A paired-samples t test will be conducted to 
compare the changes in scores in the trained tasks to investigate the training efficacy. 
The performance change of the trained tasks will be further correlated with the 
neuropsychological 
change. 
To 
test 
whether 
the 
training 
will 
improve 
neuropsychological performance in the control group, correlation analysis will be 
conducted between the performance of trained tasks and the neuropsychological change. 
To determine the training transfer effect, a series of 2 × 2 ANOVAs will be conducted 
with group and time points as the two factors. For all analyses, significance levels will 
be set to 0.05, and effect sizes refer to partial η-square values. Statistical analysis will 
be conducted using SPSS20.0 software. Imaging data will be analyzed using FSL to 
detect any changes in brain function and structure due to cognitive training.