Trial design

This study is a two-arm, multicentre, double-blind, randomised, active-controlled clinical trial. In this trial, 200 older (≥60 years) patients with MCI and hypertension will be randomised into an intervention group (multidomain adaptative CCT) and an active control group (non-adaptive, primary difficulty level programme) by a 1:1 ratio to receive a 12-week cognitive training programme. The primary outcome is the change in global cognitive function measured at 12 weeks. Patients who have completed their 12-week training in the intervention group will be further randomised into the continuation and discontinuation training groups to study the long-term effects of CCT on cognitive function. All participants will be followed up for 24 weeks. The flow chart of the trial is shown in figure 1. This trial was designed in line with the Consolidated Standards of Reporting Trials and the Declaration of Helsinki Ethics.

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Figure 1

Flow chart. MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment Scale.

Study setting

The DELIGHT trial, a large-sample, multicentre, randomised, actively controlled trial, will be conducted in 11 experienced cardiovascular cognitive centres in China, including Beijing Anzhen Hospital of Capital Medical University, Ruijin Hospital of Shanghai Jiao Tong University School, the First Affiliated Hospital of Xi'an Jiaotong University, the First Affiliated Hospital of Dalian Medical University, Jiangsu Provincial Government Hospital, the Third Hospital of Peking University, the First Hospital of Jilin University, West China Hospital of Sichuan University, Fuxing Hospital of Capital Medical University, Beijing Changping District Hospital and Ruyang County People’s Hospital.

Study population

Hypertensive patients older than 60 years of age who complained of cognitive decline in the past year will be screened from the clinical department of hypertension or cardiology of the participating hospitals. In total, 200 patients with both hypertension and MCI will be enrolled. Hypertension was defined as a previous diagnosis of hypertension in their medical record, taking antihypertensive agents, or the mean of three office blood pressure measurements≥140/90 mm Hg at the screening assessment. Two validated screening tools for MCI, namely the Montreal Cognitive Assessment Scale (MoCA)20 and Mini-Mental State Examination (MMSE),21 will be performed by trained physicians for screen and diagnosis of MCI. According to the current guidelines,22 patients with an MoCA Score<26 and MMSE Score≥24 will be diagnosed as MCI and eligible for enrolment into the trial.

Inclusion/exclusion criteria

Box 1 shows the inclusion and exclusion criteria of the randomised patients. The inclusion criteria will be an age older than 60 years, having 6 years or more education, diagnosis of hypertension, subjective cognitive complaints within 1 year (ie, memory or other cognitive complaints), MoCA Score<26 out of 30 and agreement to participate in this study. Patients with a history of vision or hearing problems, diabetes mellitus, major psychiatric or neurological illness including Parkinson’s disease, a dementia diagnosis of any type or MMSE Score<24, lack of ability to use digital equipment and so on will be excluded. Depression will be assessed using the 15-item Geriatric Depression Scale. A diagnosis of major depressive disorders is an exclusion criterion.

Sample size calculation

The sample size was calculated according to the following hypotheses. (1) The intervention group could achieve the defined improvement in global cognitive function in 30% of participants after 12 weeks of intervention.23 (2) The control group could achieve overall cognitive function improvement in 10% of the participants. (3) A two-sided test will be performed with an alpha of 5%, power of 90% and dropout rate of 20%. The number of required patients would be 99 per group with a 1:1 allocation. We therefore decided to recruit 200 subjects for the trial.

Randomisation

Patients will be randomised with a central web-based randomisation system system and with the stratification for the two major risk factors for cognitive decline, that is, age (≥75 years old, <75 years old) and educational level (completed junior high school and below, high school and above).24 The randomisation will be completed when the patient has logged into his/her account for the first time at the baseline visit after the baseline data collection. Within each stratum, the enrolled patients will be randomised at a 1:1 ratio into the ‘adaptive CCT group’ and ‘active control group’, respectively.

After completing the 12-week training session and follow-up assessment, patients in the adaptive CCT group will be rerandomised with the simple randomisation approach. One half will discontinue the interventions at 12 weeks, and another half will continue the CCT for another 12 weeks till the final assessment.

Blinding

The study investigators, physicians, outcome assessors and patients will be blinded to the treatment allocation till the 12-week follow-up assessment is finished. Blinding will be maintained for data management, outcome assessment and analysis. The trained questionnaire assessors and the imaging technicians of the brain MRI are also blinded to the randomisation.

Procedures

The computer application for cognitive training in this study offers a comprehensive cognitive training programme. Patients will be asked to train themselves independently at home for at least 5 days/week and 30 min/day. Patients will receive training for the same total amount of time each day and the same training frequency for both randomisation groups. A research coordinator will supervise the training progress on the internet. The patients will receive a call as a reminder if they have not completed the required training for 2 consecutive days. During the training process, the system will collect the training status and record the training duration and completion status.

Digital CCT

Patients in the adaptive CCT group will receive a tablet embedded with the digital adaptive algorithm training application for individualised training tasks involving multidomain of cognitive function, including attention, memory, executive function, thinking, processing speed and perception. Each task is designed with several difficulty levels (very low, low, medium, medium-high, high and very high). The tasks will be further grouped in each domain with varied task difficulties. Initially, the training will start from the ‘very low’ level for all participants and elevate to the next level when the required accuracy rate is achieved. The embedded algorithm will gradually deliver training tasks selected from the task pool per training day according to the patient’s weak cognitive domain and brain network theory. The system would adjust the difficulty level according to the real-time training performance of each individual.

The control group will also receive a tablet embedded with a cognitive training application for basic cognitive training tasks set at a non-adaptive, fixed and primary difficulty level. On each training day, the system will randomly select five training tasks from the training pool of nine training items covering the essential cognitive domains, including attention and memory.

Primary outcome

The primary outcome is the global cognitive function improvement measured by the Basic Cognitive Aptitude Tests (BCATs) at 12-week follow-up. Cognitive function improvement is the z value of the overall post-training BCATs score higher than the z value at baseline by 0.67 SDs (which indicates 2 points or higher).

The BCATs platform is an internet-based cognitive function test designed and validated by the Institute of Psychology, the Chinese Academy of Social Sciences.25 The BCATs platform is a computerised neuropsychological test with innovative analysis of time-related cognitive performance patterns. In this study, four cognitive domains will be assessed by the BCATs platform for each enrolled patient, including processing speed, working memory, situational memory and visuospatial function. Trained assessors will provide standardised instructions to the patients and help them understand the assessment rules. After completing the assessment, the platform will produce normalised cognitive domain scores.

Secondary outcomes

The secondary outcomes include the proportional improvement in overall cognitive function at 24-week follow-up compared with baseline; the proportional improvement in cognitive function compared with baseline for the subcognitive domain at 12-week and 24-week follow-up; the change in overall cognitive function scores, the patient’s self-efficacy scores, the patient’s quality of life scores, the patients’ anxiety and depression scores at 12-week and 24-week follow-up. The details are shown in table 1.

Exploratory outcome

Exploratory outcomes are the neuroplasticity changes, as measured by 7.0 T MRI. Appropriately selected participants enrolled in centres in Beijing (Anzhen Hospital, the Third Hospital of Peking University and Fuxing Hospital) and a centre in Shanghai (Ruijin Hospital) will undergo 7.0 T MRI-related imaging.

Data collection

Investigators will collect data on demographics, medication history, MoCA and MMSE scores to assess inclusion and exclusion criteria at screening. Eligible patients will be enrolled, and the following data will be collected at baseline: lifestyle (smoking, alcohol consumption and exercise), health-related quality of life (evaluated by European Five-Dimensional Health Scale (EQ-5D-3L), Patient Health Questionnaire Depression Scale (PHQ-9), Generalized Anxiety Scale (GAD-7) and Functional Activities Questionnaire (FAQ), cognitive assessment (BACTs), vital signs and physical examinations, blood samples, echocardiogram, ECG and MRI of the brain.

Blood samples will be collected for measurements of glucose, routine blood test, liver function (aspartate aminotransferase and alanine aminotransferase), renal function (urea nitrogen, creatinine and uric acid), lipids (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides).

A follow-up assessment will be scheduled after 12 weeks and 24 weeks of cognitive training, including BCATs, concomitant medications, adverse events, health-related quality of life and MRI of the brain. MRI of the brain will be performed to acquire structural images (T1 MPR), T2 Space, Resting BOLD functional images, diffusion tensor imaging (DTI), 3D-FLAIR imaging and time of flight (ToF) imaging.

Neuropsychological assessment

The neuropsychological evaluation includes several commonly used measures of the quality of life. Measures include the Chinese version of the General Self-Efficacy Scale (GSES), the EQ-5D-3L, the PHQ-9 and the GAD-7. The GSES26 consists of 10 items and is scored on a 4-point Likert scale from 1 (‘strongly agree’) to 4 (‘strongly disagree’). Q-5D-3L27 is a self-rating scale for measuring quality of life consisting of five dimensions: mobility, ability to take care of oneself, ability to perform daily activities, pain or discomfort and depression. Each dimension has three categories of options (normal, moderately limited and severely limited). The PHQ-9 Scale28 is a self-rating scale of depressive symptoms recommended by the AHA Advisory Panel on Depression and Coronary Heart Disease, which has good subject acceptance. The GAD-729 is a simple, operational quantitative assessment tool recommended in the Design Standards Manual-V (DSM-V) published by the American Psychiatric Association.

The electronic date capture (EDC) system will be used to facilitate date collection and monitoring in this study. After finishing the baseline and follow-up visits, the investigators and coordinators will enter the required data in the EDC system. The monitors will independently review the source documents regularly and check if the data entered are complete and accurate.

MRI protocol

Selected patients recruited from Beijing and Shanghai will undergo MRI of the brain at baseline and at 12-week and 24-week follow-up. MRI sequences will be provided as a guideline for the standardisation of MRI acquisition across centres. Each participating centre will be required to submit a test scan of a volunteer for technical approval before the enrolment of patients.

MRI data will be obtained by Siemens MAGNETOM 7.0T MRI scanner using a standard head coil by an experienced radiologist. During the scan, patients will not perform any tasks and will be asked to close their eyes, breathe smoothly and keep their heads as steady and still as possible.

The MRI sequences and their specific parameters are as follows.

1. High-resolution T1-weighted images of the whole brain will be obtained using a Magnetization Prepared-Rapid Gradient Echo sequence: repetition time (TR)=2600.0 ms, echo time (TE)=3.41 ms, voxel size=0.6×0.6×0.6 mm, slice thickness=0.60 mm and slice number=256, flip angle (FA)=8°.

2. Resting-state functional MRI will be performed using a multiband echo-planar imaging (EPI) sequence: TR=1400 ms, TE=22.00 ms, voxel size=1.5×1.5×1.5 mm, slice thickness=1.5 mm and slice number=84, FA=60°.

3. The DTI will be acquired by using a diffusion-weighted double spin-echo EPI sequence: TR=5200 ms, TE=83.0 ms, voxel size=1.2×1.2×1.2 mm, slice thickness=1.2 mm and slice number=120, FA=90.

4. Flair-space sequence parameters: TR=8000 ms, TE=402 ms, voxel size=0.6×0.6×0.6 mm, slice thickness=0.60 mm and slice number=256.

5. TOF_0.4iso_p3 sequence parameters: TR=15.0 ms, TE=4.09, voxel size=0.4×0.4×0.4 mm, slice thickness=0.4 mm and slice number=44, FA=20.

6. T1W_Space sequence parameters: TR=1150 ms, TE=39.0 ms, voxel size=0.4×0.4×0.4 mm, slice thickness=0.4 mm and slice number=352.

Incentives and retention

Each participant will be given a free account for 1-year access to the online cognitive training after completing a 24-week assessment. Participants will receive a transportation subsidy for the clinic follow-up visits.

Statistical analyses

The two randomisation groups will be compared for baseline demographics, educational level, morbidities, cognitive performance, mental health performance, blood pressure, cardiac function and blood chemistry. Continuous variables will be expressed as means values and SDs and compared between groups using the unpaired t-tests. Non-normally distributed data will be expressed as median (IQR) and log-transformed for analysis. If after log-transformation normal distribution is still skewly distributed, the non-parametric analysis will be performed. Qualitative variables will be expressed as counts and proportions and compared between groups using the χ² test.

The primary hypothesis of this study is that adaptive CCT will enable a higher proportion of patients to achieve an overall cognitive improvement than non-adaptive training. The overall cognitive improvement will be treated as a dichotomous variable, defined as a z value of the post-training BCATs Score higher than the z value at baseline by 0.67 SDs. Longitudinal logistic regression will be used to estimate treatment effects. For the analyses of secondary endpoints, we will use generalised linear mixed effects models to compare the cognitive and neuropsychological measurements collected at baseline and at 12-week and 24-week follow-up, and the time will be treated as a categorical variable in the model. The statistical analysis will be performed according to the intention-to-treat principles. The study site and the stratification variables, that is, age group and educational level, will be included in the analysis as covariates.

An exploratory analysis will also be performed to investigate potential changes in MRI, including intracranial volume, hippocampal volume, frontal grey matter volume, cerebral blood flow, functional connectivity and so on, which will be analysed between groups using the generalised linear mixed-effect models with time, age group and educational level as covariates. The exploratory outcomes of interest will include the volume and thickness of hippocampus, basal ganglia and thalamus, and the intranetwork and internetwork functional connectivity between the relevant cortical and subcortical networks on the basis of the results of previous research that has shown potential neuropsychological mechanisms on hypertension-related cognitive impairment30 and cognitive training-induced improvement.15

Handling of missing data

A stringent quality assurance procedure was applied to assure the completeness of data collection. Missing values will be treated according to the Molenberghs and Kenward approach.10 The maximum likelihood method will be employed in the parameter estimation if the missing meets the random missing mechanism. If necessary, other methods will be considered to determine whether the results are reliable and provide an appropriate conservative estimate.

Sensitivity analyses will also be performed to further explore the reliability of missing value data inferences, and examine several ‘worst case’ scenarios, including opposite and pooled estimation methods. These phenomena can be parameterised into mixed models and allow for testing the sensitivity of findings to non-random missingness mechanisms.

Safety and reporting of adverse events

Cognitive assessment and training are usually safe for patients. No adverse or serious adverse events are expected to be attributable to the intervention during the study. Investigators will be requested to keep detailed records of any adverse events, including a description of the adverse event and associated symptoms, time of occurrence, seriousness, cause of the adverse event, correlation with cognitive training, duration, actions taken and outcome and regression.

Patient and public involvement

During the study enrolment stage, patients were referred for initial screening visits to the study through cardiologist referral or self-referral through online and hospital recruitment advertisements. Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this study. Patients will only be involved as research participants and individual feedback on their research participation will be given.

Ethics and dissemination

The study protocol (V.1.3; date: 15 March 2023) was reviewed and approved by the ethics committee at the institutional review board of Beijing Anzhen Hospital, and thereafter by all participating centres. Necessary modifications will be made to the protocol after the research group reaches a consensus and should be approved by ethics committees before implementation. Written informed consent (online supplemental file 1) will be obtained from all participants by trained investigators. Patients’ data will be deidentified before entry into the database to protect the privacy. Project principal investigators will have access to their own site’s cleaned dataset. Trial findings will be disseminated in peer-reviewed journals and conference presentations.