Effectiveness of an Individualized Exergame-Based Motor-Cognitive Training Concept Targeted to Improve Cognitive Functioning in Older Adults With Mild Neurocognitive Disorder: Study Protocol for a Randomized Controlled Trial

Background Simultaneous motor-cognitive training is considered promising for preventing the decline in cognitive functioning in older adults with mild neurocognitive disorder (mNCD) and can be highly motivating when applied in the form of exergaming. The literature points to opportunities for improvement in the application of exergames in individuals with mNCD by developing novel exergames and exergame-based training concepts that are specifically tailored to patients with mNCD and ensuring the implementation of effective training components. Objective This study systematically explores the effectiveness of a newly developed exergame-based motor-cognitive training concept (called “Brain-IT”) targeted to improve cognitive functioning in older adults with mNCD. Methods A 2-arm, parallel-group, single-blinded randomized controlled trial with a 1:1 allocation ratio (ie, intervention: control), including 34 to 40 older adults with mNCD will be conducted between May 2022 and December 2023. The control group will proceed with the usual care provided by the (memory) clinics where the patients are recruited. The intervention group will perform a 12-week training intervention according to the “Brain-IT” training concept, in addition to usual care. Global cognitive functioning will be assessed as the primary outcome. As secondary outcomes, domain-specific cognitive functioning, brain structure and function, spatiotemporal parameters of gait, instrumental activities of daily living, psychosocial factors, and resting cardiac vagal modulation will be assessed. Pre- and postintervention measurements will take place within 2 weeks before starting and after completing the intervention. A 2-way analysis of covariance or the Quade nonparametric analysis of covariance will be computed for all primary and secondary outcomes, with the premeasurement value as a covariate for the predicting group factor and the postmeasurement value as the outcome variable. To determine whether the effects are substantive, partial eta-squared (η2p) effect sizes will be calculated for all primary and secondary outcomes. Results Upon the initial submission of this study protocol, 13 patients were contacted by the study team. Four patients were included in the study, 2 were excluded because they were not eligible, and 7 were being informed about the study in detail. Of the 4 included patients, 2 already completed all premeasurements and were in week 2 of the intervention period. Data collection is expected to be completed by December 2023. A manuscript of the results will be submitted for publication in a peer-reviewed open-access journal in 2024. Conclusions This study contributes to the evidence base in the highly relevant area of preventing disability because of cognitive impairment, which has been declared a public health priority by the World Health Organization. Trial Registration ClinicalTrials.gov NCT05387057; https://clinicaltrials.gov/ct2/show/NCT05387057 International Registered Report Identifier (IRRID) DERR1-10.2196/41173

Roles and responsibilities 5a Names, affiliations, and roles of protocol contributors Discussion -Authors' Contributions 5b Name and contact information for the trial sponsor Methods -Trial Design and Study Setting (Table 1) 5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions

Methods -Randomization -Sequence Generation
Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

Methods -Randomization -Allocation Concealment Mechanism
Implementation 16c Who will generate the allocation sequence, who will enroll participants, and who will assign participants to interventions

Methods -Randomization -Implementation
Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how Definition of analysis population relating to protocol non-adherence (eg, as randomized analysis), and any statistical methods to handle missing data (eg, multiple imputation)

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed

Methods -Monitoring 21b
Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial

Harms 22
Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct

Methods -Outcomes -Other Endpoints -Safety Endpoint Variables
Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor N/A

Ethics and dissemination:
Research ethics approval 24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval

Methods -Ethics Approval and Ethics and Methods -Ethics and Dissemination -Research Ethics Approval and Protocol Amendments
Protocol amendments 25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)

Methods -Ethics and Dissemination -Research Ethics Approval and Protocol Amendments
Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorized surrogates, and how (see Item 32) Methods -Ethics and Dissemination -Consent or Assent 26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable N/A

Confidentiality 27
How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial

Data collection and documentation
What data will you collect, observe, generate or re-use?
In this research project, the following quantitative data is recorded directly on the electronic case report forms (eCRF), in a separate source document (for all study centers data is locally stored on a secure ETH server of the RCT/3_Data & Statistics/2_Data), or in paper format (e.g. questionnaires) in the trial master files. Selected data (all data collected except MRI data and data of the adherence and compliance protocol for the exergame group) will be transmitted to the eCRFs and will be exported for statistical analysis as CSV files. This includes the following: • How will the data be collected, observed or generated?
Data collection of all clinical outcome measures as well as the demographic and clinical characteristics of the study participants will be done by outcome assessors who will be thoroughly trained by the local principal investigators in using the measurement technologies and protocols as well as data management according to the Guidelines of Good Clinical Practice and considering detailed working instructions. The local principal investigators will be in charge for the methodological standards and quality of the data collection. To ensure that the outcome assessor of all clinical outcome measures is not influenced by the group allocation of the measured participant, the outcome evaluator of the pre-, and post-measurements will be blinded to group allocation. To minimize bias during the assessment of all clinical outcome measures, detailed working instructions were prepared that include standardized procedures and instructions of participants for all measurements as well as standardized procedures of data management, evaluation, and storage (including standardized naming conventions for the structure of folders and file names to organize the data). Whenever possible, validated measurement protocols were selected for this study and (if available) will be administered according to standardized protocols of developers/manufacturers. Data of all clinical outcome measures as well as the demographic and clinical characteristics will be recorded directly on the electronic case report forms (eCRF) or in a separate source document and on the electronic case report forms. The project leader will be in charge of setting up the eCRF using the data management system Castor EDC (Ciwit BV, Amsterdam, The Netherlands) [3]. The investigators will create eCRFs, one for each enrolled study participant, to be filled in with all relevant data pertaining to the subject during the study. The eCRF will only contain coded identification so that participants are not identified on the document by name or birth date and to ensure subject confidentiality. Appropriate coded identification will be used (i.e. an eight-digit random number will be generated by the data management system Castor EDC (Ciwit BV, Amsterdam, The Netherlands) [3] to encode each participant within the eCRF. It will be assured that any authorized person, who may perform data entries and changes in the eCRF, can be identified. All changes within the eCRF will automatically be reported in an audit trial by the data management system Castor EDC (Ciwit BV, Amsterdam, The Netherlands) [3]. The Audit Trial shows all changes that are made to the study, including changes both during building the form and during data entry. The investigators assure to perform a complete and accurate documentation of the participants' data in the eCRF. During the study, the eCRFs will be kept updated to always reflect the current participant status. Additionally, all data entries will be cross-checked by a second study investigator prior to export for analysis and range checks for data values were pre-programmed for data entry in the eCRF. All generated data will always be stored twice/double at the Data collection of all additional endpoints (i.e. adherence protocol, implementation evaluation, and cost effectiveness) will be done the following: The quantitative data on the adherence protocol will be collected by the responsible persons for supervision and correspondence with study participants using training logs and forms, including the number and duration of (completed) training sessions. All generated data will always be stored twice/double at the investigational sites (Institute of Human Movement Science and Sports, ETH Zurich or Department of Health, Eastern Switzerland University of Applied Sciences) in pseudonymized form on a secure network folder.
What documentation and metadata will you provide with the data?
For each dataset, a README file will be provided, including the name and persistent identifier of each dataset file, the date and time of data collection, and the names of the persons who collected the data. In addition, the data processing methods, analytical steps, and person identifier for persons involved in data processing or analytic steps, and assessments, if applicable, will be provided. The conditions to access the data will also be provided, such as a creative commons license.

Ethics, legal and security issues
How will ethical issues be addressed and handled?
Personal data and health-related data are sensitive personal data by the Swiss Federal Act on Data Protection.
All trial and participant data will be handled with uttermost discretion and will only be accessible to authorized personnel who require the data to fulfil their duties within the scope of the study. All information of participants obtained because of this study will be considered confidential and disclosure to third parties is prohibited. All the investigators of the study are bound to professional discretion. Furthermore, all procedures must comply with the current Good Clinical Practice standards, the Declaration of Helsinki and the Swiss Human Research Act.
All potential subjects will be fully informed about the study procedures by providing verbal explanations and an information sheet. The purpose of the study as well as expected effects, benefits and risks of the study will be explained by the investigators, who will also be available to answer open questions and clarify uncertainties of participants. It will further be verified, that withdrawal is permitted at any time during the study without having to give a reason, highlighting that participation in the study is entirely voluntary. The study information sheet will include detailed information on data collection, storage, processing, and sharing/publication and will inform about a participants' right on information about the collected data as well as data deletion and data correction.
Personal data of participants will be encoded before recording, which makes it impossible to conclude on the individual research data without the subject master file (including the pseudonymization codes) and the randomization log. Only the leading project manager and the local principle investigators will be assigned the rights Supplementary Files -Study Protocol 'Brain-IT' RCT 10/13 Version 1.0, 20 July 2022 Study ID = 2022-00386 to view the randomization log within the eCRF (data management system Castor EDC (Ciwit BV, Amsterdam, The Netherlands) [3]).
The investigators will create a record in the electronic case report forms (eCRF) using the data management system Castor EDC (Ciwit BV, Amsterdam, The Netherlands) [3], one for each enrolled study participant, to be filled in with all relevant data pertaining to the subject during the study. The eCRF will only contain coded identification so that participants are not identified on the document by name or birth date and to ensure subject confidentiality. Appropriate coded identification will be used (i.e. an eight-digit random number will be generated by the data management system Castor EDC (Ciwit BV, Amsterdam, The Netherlands) [3] to encode each participant within the eCRF. It will be assured that any authorized person, who may perform data entries and changes in the eCRF, can be identified. All changes within the eCRF will automatically be reported in an audit trial by the data management system Castor EDC (Ciwit BV, Amsterdam, The Netherlands) [3]. The Audit Trial shows all changes that are made to the study, including changes both during building the form and during data entry. The investigators assure to perform a complete and accurate documentation of the participants' data in the eCRF. During the study, the eCRFs will be kept updated to always reflect the current participant status. All data entries will be cross-checked by a second study investigator prior to export for analysis.
Exported data will still be encoded using the coded identification and will always be stored twice/double at the investigational sites (Institute of Human Movement Science and Sports, ETH Zurich or Department of Health, Eastern Switzerland University of Applied Sciences) on a secure network folder. Trial and participant data will be handled with uttermost discretion and will only be accessible to authorized personnel who require the data to fulfil their duties within the scope of the study. All information of participants obtained because of this study will be considered confidential and disclosure to third parties is prohibited. All the investigators of the study are bound to professional discretion. All study investigators will be thoroughly trained for data management according to the Guidelines of Good Clinical Practice and considering detailed working instructions. Additionally, data entry will be cross-checked by a second study investigator and range checks for data values will be preprogrammed for data entry in the eCRF.
For quality assurance the sponsor, the Ethics Committee or an independent trial monitor may visit the research sites. Direct access to the source data and all study related files is granted on such occasions. All involved parties keep the participant data strictly confidential.
The protocol of the study was approved by the Ethics Committee of Zurich and Ethics Committee of Eastern Switzerland (EK-2022-00386). The study will be conducted according to the study protocol, the Declaration of Helsinki, the principles of Good Clinical Practice, and the Human Research Act.
How will data access and security be managed?
All research data will always be stored twice/double at the investigational sites (Institute of Human Movement Science and Sports, ETH Zurich or Department of Health, Eastern Switzerland University of Applied Sciences)