The RenAtt Method for Diagnosing and Treating Attention Problems After Stroke and Brain Injury, Further Validation of RehAtt® DiSTRO Assessment of Cognitive and Visual Function

The Oxford Cognitive Screen (OCS) (Demeyere et al., 2015) provides a multi-domain, stroke specific screen, and was designed as a first-line screening tool to determine the extent of focal cognitive deficits incurred by the stroke. Whilst the OCS has seen a wide take up in acute stroke-specific settings, its length (approx. 20 min) and focus on acute deficits such as hemispatial neglect, apraxia, reading/writing impairments, as well as its inclusive nature (no penalties for using multiple choice responses in order to not unfairly penalise patients with aphasia), means it works well as a first line screening tool to detect the immediate effects of the stroke. One issue with the paper OCS is time to prepare for using the OCS in terms of training and materials, administering the OCS, and scoring the OCS all take time, even with handy templates to reduce time burden. Authors of the OCS, estimate the preparation time takes around 15 minutes if printing all materials and preparing documents, and then scoring takes around another 10 to tally up marks, make notes, and correctly classify subtasks are impaired or not compared to normative data.

Using a digital version of the OCS could offer a more precise and controlled presentation of tests and stimuli as well as reduce total time taken due to quick availability and automated scoring.

The widespread adoption of tablet computers has facilitated cost-effective computerized cognitive assessment tools . Computerized cognitive assessments present several important advantages over pencil-and-paper-based assessments, including the standardization of test administration, recording of more detailed response metrics, and automated scoring . In addition, previous researchers have called for tools with automated scoring and reporting to reduce the potential for scoring and data entry errors, and to facilitate real-time evaluation of standardized performance . Previously, made a computerised extension of the OCS called the OCS-Plus, which was developed to more specifically target memory and executive function impairments following stroke.

Currently, Oxford University Innovation has licensed a digital version of Oxford Cognitive Screen www.psy.ox.ac.uk), OCS to be developed. This has now had an approval to be identical to the paper and pen traditional version. The DiSTRO electronic OCS (electronic OCS) is now available as a software applied on a 13´-tablet computer, a CE marked product. When generating new digital formatted assessments of traditionally pen-and-paper tasks, it is typical to validate such modality shifts by comparison to the original. Should differences be found between the two formats that are not attributable to a genuine change in performance over modality, the digital version must adapt until it is equivalent to the original. Once equivalence is found, the pen-and-paper version may be swapped out for the more efficient and accurate digital version. As mentioned, there are clear advantages to digital formats in terms of; quicker administration, automatic task presentation, more accurate reaction time measurement, automation of scoring and reacting to correct and incorrect answers, and above all standardised presentation of the whole test. These reductions in time naturally free up healthcare professionals time to complete other clinically relevant tasks. In a world where clinical time is stretched already, introduction of a digital tool is a clear benefit to healthcare professionals, worldwide.

Aim of the study The aim is to validate the computer tablet based DiSTRO electronic OCS within subacute stroke population, to establish reliability, by comparing results from the traditional paper and pen OCS to the electronic OCS, as well as compare the patients' results with those of the healthy controls. Stroke survivors early post-stroke were chosen as the most appropriate sample due to usual administration time of the OCS in real world and research . A secondary aim was to evaluate the feasibility and cost-effectiveness of using this computerized cognitive screening tool for stroke, to ensure it is easy to use for the patient and healthcare professionals and provides value for money.

Primary objective To validate accuracy of the DiSTRO digital version of Oxford Cognitive Screening vs. the traditional OCS. To achieve this objective, we will compare the orginal pen-and-paper Oxford Cognitive Screen (OCS) to the new computer tablet OCS (electronic OCS).

The hypothesis is that the electronic OCS will be equivalent with the original pen-and-paper format of the OCS in acute stroke survivors. Due to the range and data type of the OCS/electronic OCS, we will use two-sided tests of equivalence (TOSTER) to establish performance with a small effect size difference as the largest effect size difference we would accept as equivalent of d=.20.

Secondary objectives To assess feasibility and cost-effectiveness of administering electronic OCS. To measure this using the Systems Usability Scale (SUS), and the Usability Metric for User Experience (UMUX), in addition to a brief health economic evaluation STUDY DESIGN To use a cross-sectional within-subjects design. Participants will be exposed to two assessment formats of the same test and to complete them in counterbalanced order where possible.

STUDY SETTING To use a multiple centre design, located at St George's Hospital in London, Danderyds Hospital Stockholm Sweden, Physical and Rehabilitative Medicine Unit,National Health Service, Grosseto, Italy. Specifically, recruit stroke survivors from the hyper acute and acute/rehab units at the hospitals.

PARTICIPANT ELIGIBILITY CRITERIA

a. Study participants Participants will be 50 + 50 + 50 stroke survivors who are within 2-weeks of their suspected or confirmed stroke admitted to the Hospitals at either the hyper acute or acute stroke wards. The sample size was chosen based on the planned analyses and the number of participants required to accurately conduct these tests. Anonymised research data will be collated with international OCS/electronic OCS data to reach statistical power to over 150 stroke survivors, Inclusion criteria

• Confirmed stroke via neuroimaging and/or clinical diagnosis
• Aged 18 years or older
• Within 48hrs or up to 2-week of confirmed clinical diagnosis of stroke (first ever or recurrent) 4) Ability to concentrate for 10 minutes, as judged by clinical team

• Sufficient English fluency 6) Able and willing to provide informed consent Exclusion criteria

• Any sensory or perception impairments (e.g., vision or hearing) which preclude the administration of OCS even with reasonable adjustments
• Any medical or psychiatric conditions or delirium that makes cognitive assessments in appropriate in the 3-day timeframe
• Severe receptive aphasia (no reliable yes/no responses (<95% correct response)

STUDY PROCEDURES

a. Recruitment, identification, and consent Healthcare professionals working at these clinics will be the first to approach potentially eligible stroke participants, based on screening of medical records for eligibility. All participants will first be asked if it is acceptable to them to be approached regarding research, and if so, the healthcare professional on the research team will continue with approach. Eligibility of participants will be assessed against the criteria in this protocol when discussing the research with a patient. If eligible, during usual-care clinical practices, healthcare professionals will conduct the informed consent procedure with stroke patients. Potential participants will be given a full verbal explanation of the study including available support from the research team and details on conducting the testing. At all times in this study healthcare team staff will be approaching and testing participants, with no external non healthcare staff used. Given that stroke patients, especially in early stroke, can have language difficulties and other forms of cognitive impairments, standard informed consent procedures will be adapted to enhance inclusion in the study. As in line with the Mental Capacity Act (2005), capacity will be assumed and instead all reasonable adjustments to the consent procedure will be made. Inclusion of stroke patients with cognitive impairment and language difficulties is important as these are the patients who are often neglected from stroke research and thus much stroke research does not reflect the clinical reality of stroke. Accessible, picture-based versions on the Participant Information Sheet and consent forms will be provided alongside the standard forms upon approaching patients. There is no time limit on inclusion as participants can decide to take part at any point in time after being identified and approached for informed consent/consultee declaration procedure. Typically, participants are given at least 24hrs once approached but due to the fast paced nature of acute stroke units, the participant can decide earlier if they wish. Capacity to consent as per the Mental Capacity Act is time and decision specific. At the time of consenting participants must have capacity to consent to take part, as assessed by the healthcare professionals in their professional capacity. Healthcare professionals will monitor for dissent to take part and ask participants in each of the two main sessions if they are happy to continue. Should a participant be deemed to not be able to answer such a question due to their mental capacity at that time, healthcare professionals will stop the session and reattempt when they are in a better position (medically fit, not suffering a UTI etc) to answer any questions or take part. If they are still unable to verbally consent to continued participation, a re-attempt will not be made, and the participant will be withdrawn but their usable data kept.

Once consented, demographic information will be collected regarding age, gender, education, ethnicity, handedness, stroke type, stroke side, disability level (modified rankin scale), and stroke severity (NIHSS). Information can mostly be gained from clinical notes and healthcare team observation except years of education which must be gathered from the participant.

We will not collect information on those who were screened for eligibility versus those who were approached versus those who consented as this is not relevant to our research study and as it is an added burden to the clinical team.

Assessments Two assessments will be used in this project; the paper OCS which is part of standard care, and the electronic OCS. If participants, at time of consent and beginning of the study have already had the OCS as part of standard care within the last 3 days, the OCS will be taken from their clinical notes. If the OCS was not completed within the last 3 days, the standard of care OCS will be completed in counter balanced order with the electronic OCS by the research team. The research team will aim to do both assessments within the same day, if possible, but if due to participant request or another reason, the assessments can be split over two sessions.

After the last participant is completed in the study, the clinical research team will fill in a single Microsoft forms held on Brain Stimulation AB servers for feedback that will combine SUS and UMUX scales. The clinical team will fill this in to reflect on their experience using the OCS and the eOCS.

Total time in the study for participants is expected to be less than 1hour depending on time taken to complete the eOCS/OCS, with an average of 40 minutes.

Payment No financial or non-financial reimbursement will be given to participants for their time.

Withdrawal criteria

Each participant has the right to withdraw from the study at any time. In addition, the Investigator may discontinue a participant from the study at any time if the Investigator considers it necessary for any reason including:

• Poor health resulting in participant no longer meeting the inclusion criteria of 10-minute concentration span (as determined by the researcher or healthcare team)
• Poor health that results in the participant being unable to complete both assessments (OCS and electronic OCS) within 3-days of each other Withdrawn participants will not be replaced. The reason for withdrawal will be reported where it is available. We will retain and analyse data collected from the participant before the point of their withdrawal. Explicit requests from participants to exclude data collected from them prior to their withdrawal from analyses will be honoured.

SAFETY REPORTING The study will involve implementation of a validated screening measure and a new version of the same measure in digital computer tablet format to briefly assess cognition. It is very unlikely that any serious adverse events (SAEs) serious adverse reactions (SARs), or serious unexpected serious adverse reactions (SUSARs) will occur as a direct result of participation in the study and it is not an objective of the study to formally evaluate this. It is possible, however, that within the study timeline, participants may develop new illnesses/diagnoses, or unfortunately pass away due to complications from the stroke itself. These negative outcomes unfortunately occur in standard stroke care practice and are thus expected to occur within the context of the study.

END OF STUDY The end of study is the date of the last participant research session.

STATISTICS AND DATA ANALYSIS

a. Sample size calculation The numbers are based upon resources available for recruitment at the three sites, site within the study timeframe and to combine with efforts post-hoc with international data. The sample numbers when combined across UK, Sweden and Italy will be appropriate for statistical tests of association between electronic OCS and OCS. For instance, 50 participants alone is not enough to correct for multiple comparisons when examining associations with each subtask of the OCS, but 150 combined with 150 health controls internationally, is sufficient for 80% statistical power. Feasibility does not have any formal power analyses for sample required.

Planned recruitment rate In concurrent international studies with different methods but similar clinical settings, we are experiencing recruitment of 2 or 3 participants a day. As our study is on top of clinical load, we anticipate recruiting anywhere between 5 and 10 participants in a calendar week., giving 6-months for this study for potential slow recruitment in the beginning due to getting used to the protocol and then fast recruitment as time goes on.

Statistical analysis plan Participant demographics (e.g., age, sex, stroke severity etc) alongside primary and secondary outcome measures will be summarised descriptively in R Studio software. Feasibility statistics such as how many participants successfully completed the electronic OCS versus the paper OCS, how long the electronic OCS took to administer, and ratings on feasibility/usability scales (SUS and UMEX) will be summarised descriptively too.

To examine our hypothesis of equiveillance between electronic OCS and paper-based OCS, parametric or non-parametric analyses techniques to establish the association between electronic and paper-based OCS such as Spearman's Rho correlations, proportions of tasks impaired across versions, and two-sided tests of equivalence methods will be used. To further examine feasibility, we will examine linear prediction models predicting accuracy by performance on electronic versus paper-based OCS, including demographic factors such as age, education, and stroke severity. To generate descriptive statistics for the SUS, and the UXM, and compare to normative reference for interpretation.

For economic investigation of cost-effectiveness, to estimate clinical time for administering the DiSTRO electronic OCS based upon administration duration, combined with training duration, and estimated scoring interpretation time by clinicians. To describe each of these facets descriptively. To compare these values to existing data for the original OCS and establish differences in NHS cost for each modality. Procedure(s) to account for missing or spurious data Any missing data will be handled using multiple imputation procedures, following determination of the missingness mechanism. For instance, if data are missing at random this will determine one form of imputation over another where data were systematically missing for any reason. Imputations will include variables of age, education, sex, and stroke severity in their prediction mechanisms. Participants whose data contain with impossible values (e.g., on a subtask with a score of 0-4, they have an entered score of 5), original source paper data copies will be consulted. We have no plans for statistical exclusion of participants. Any missing data will be noted by clinicians on the CRF for each participant. Imputed datasets will be compared and if DATA MANAGEMENT

• The plan for the data management of the study is outlined below. There is not a separate Data Management document in use for the study.
• Source Data Source data is defined as where data are first recorded, and from which participants' data are obtained. These include, but are not limited to, hospital records (e.g., stroke medical history), participant self-reported demographic data on the eCRF, and records of clinical assessments/study measures. All documents will be stored safely in confidential conditions accessible only by authorised individuals. On all study-specific documents, other than the signed consent form, the participant will be referred to by a unique participant identifier, not by participant name or any other title that may otherwise compromise confidentiality.

Data handling and record keeping Once consent is given/a consultee declaration form has been completed we will allocate a unique participant identifier (PID) to each participant. There will be electronic and paper versions (held at study sites for ease of use by HCPs) of the key linking names with participant numbers. Only the participant number and never the name, address etc. will be used on all other documents and electronic records (outcome measures, interviews, etc.) in the study except in consent form/declaration form where name of participant will be included. If participants do not consent to take part or withdraw from the study, any records of their name will be immediately deleted. Password protected electronic records of anonymised data to which the healthcare research team and researchers will have access will be stored securely. Because unique participant identifiers (PID) are considered personal identifiable data under GDPR, PID will be stored for 12 months following the end of the study. Further participant contacts details like name will be retained for this period (in case of missing assessment data/missing medical record data) and permanently deleted following the 12-month mark. In the participant information sheet, it is explained what data is kept and for how long, as well as how any anonymised data will be used.

For feasibility assessments with the SUS and UMUX, the data will be collected anonymously via MS forms, and it will not store any PID, ID, or location/IP information about the clinical research team member completing the assessment. The forms will be downloaded and stored in PDF format for up to 3 years on Brain Stimulation AB secured encrypted servers. The results of the questionnaire will be summarised in a spreadsheet for analyses, and also shared on Open Science platforms as it is anonymised data.

Any clinical data obtained from medical records (e.g., stroke type, stroke severity scores) will similarly be stored using the unique participant identifier and will not be tied to participant names or other personally identifiable information. No hard copies of medical record information will be taken from participating NHS sites and instead all data taken from medical records will be transformed into numeric variables (e.g., age in years rather than date of birth) to reduce the risk of identification of any individual participant from this data. Throughout the duration of the study, a unique participant identifier will be used to match research data (e.g., between files collecting medical record data and questionnaire data) to maintain a single master dataset without the need to use any other personal information. Once the study is completed and the 12-month timeline for retaining pseudonymised data has arrived, these unique participant identifiers will be removed from dataset records, creating an anonymised dataset for upload onto Open data servers.

d. Access to Data Direct access will be granted to authorised representatives from the Sponsor, host institution and the regulatory authorities to permit study -related monitoring, audits and inspections- in line with participant consent.

ETHICAL AND REGULATORY CONSIDERATIONS

a. Declaration of Helsinki The Chief Investigator (Dr Helena Fordell) will ensure that the studies are conducted in accordance with the principles of the Declaration of Helsinki.

b. Guidelines for Good Clinical Practice The Chief Investigator will ensure that the study is conducted in accordance with relevant regulations and Good Clinical Practice.

c. Approvals Following Sponsor approval, the protocol, informed consent form/consultee declaration form, participant information sheet and other study documents will be submitted to an appropriate Research Ethics Committee (REC), HRA and host institutions for written approval prior to beginning recruitment. The Investigator will submit and, where necessary, obtain approval from the above parties for all substantial amendments to the original approved documents. Detailed records of correspondence with the REC, and annual reports, will be completed as necessary and stored in the site file.

d. Other Ethical Considerations The intervention described here is conducted in addition to services typically offered within the stroke care pathway. The study will not therefore deprive participants of other beneficial interventions and care they may be accessing outside of the study .

e. Reporting The Chief Investigator shall submit once during the study timeline, or on request, an Annual Progress report to the REC Committee, HRA (where required) host organisation, Sponsor and funder (where required). In addition, an End of Study notification and final report has been submitted to the same parties. The REC and Sponsor has been notified. No adverse events happened, non to be reported.

Participant Confidentiality The risk of a breach of confidentiality is managed by the research being conducted in accordance with best practice. The study will comply with the UK General Data Protection Regulation (GDPR) and Data Protection Act 2018 (and 1998), which require data to be deidentified as soon as it is practical to do so. The processing of the personal data of participants will be minimised by making use of a unique participant study number only on all study documents and any electronic database(s) with the exception of consent form/declaration form where participant name will be added. All documents will be stored securely and only accessible by study staff and authorised personnel. The study staff will safeguard the privacy of participants' personal data.

i. Public and Patient Involvement Stroke survivors has been consulted in the design of the electronic OCS (tablet application under investigation). We will further consult different independent stroke survivors and their caregivers on dissemination of results.

j. Protocol Deviations A study related deviation is a departure from the ethically approved study protocol or other study document or process (e.g., consent process or administration of study intervention) or from Good Clinical Practice (GCP) or any applicable regulatory requirements. Any deviations from the protocol will be documented in a protocol deviation form and filed in the study master file.

In the context of the study protocol deviations may include (but are not limited to) use of non-ethically approved assessments, more than typical assessment sessions (e.g., 3 sessions to complete tasks not 2 due to participant fatigue), deviations from the informed consent procedure/consultee advice procedure or failing to recruit participants in accordance with inclusion/exclusion criteria. Protocol deviations will be monitored by regular meetings between participating sites and study staff, as well as through direct report from health care professionals involved in the study conduct. Any protocol deviations, whether accidental or intentional, will be documented and reported to the Chief Investigator and Sponsor immediately. Immediate action will be taken to resolve non-compliance.

k. Notification of Serious Breaches to GCP and/or the protocol A "serious breach" is a breach which is likely to effect to a significant degree - • the safety or physical or mental integrity of the participants of the study • or the scientific value of the study

In the event that a serious breach is suspected the Sponsor will be contacted within 1 working day. In collaboration with the Chief Investigator, the serious breach will be reviewed by the Sponsor and, if appropriate, the Sponsor will report it to the approving REC committee and the relevant NHS host organisation within seven calendar days'.

FINANCE AND INDEMNITY Nele Demeyere is a developer of the "Oxford Cognitive Screen", used in this study, but does not currently receive any remuneration from its use. The concept and IP have been registered with Oxford University Innovations, who holds the copyright to the screen. Helena Fordell is the Founder of Brain Stimulation AB, the company funding this research and the creator of the DiSTRO- electronic OCS. Helena Fordell and Nele Demeyere may receive financial remuneration for the use of DiSTRO- electronic OCS in the future. Brain Stimulation will provide public and professional liability insurance (via Chubb European Group SE).

Only anonymised data will be kept in the long-term. Physical copies of anonymised data will be stored locally within the St George's Hospital for 3 years, as per institutional positives minimum time for paper-based anonymised data. When data are made open, in principle they are preserved indefinitely. Therefore, although we have put down 3 years as an institutional limit for research data, the anonymised data will be stored as open access files online indefinitely. The long-term storage of anonymised data will be communicated to participants at the point of consent.

Inclusion criteria

• Confirmed stroke via neuroimaging and/or clinical diagnosis
• Aged 18 years or older
• Within 48hrs or up to 2-week of confirmed clinical diagnosis of stroke (first ever or recurrent) 4) Ability to concentrate for 10 minutes, as judged by clinical team

• Sufficient English/Italien/Swedish fluency 6) Able and willing to provide informed consent Exclusion criteria

• Any sensory or perception impairments (e.g., vision or hearing) which preclude the administration of OCS even with reasonable adjustments
• Any medical or psychiatric conditions or delirium that makes cognitive assessments in appropriate in the 3-day timeframe
• Severe receptive aphasia (no reliable yes/no responses (<95% correct response)