The Impact of Cognitive Function on Virtual Reality Intervention for Upper Extremity Rehabilitation of Patients With Subacute Stroke: Prospective Randomized Controlled Trial With 6-Month Follow-up

Background Stroke is among the leading causes of long-term disability worldwide. Motor impairments after stroke not only impact the individuals quality of life but also lay substantial burdens on the society. Motor planning is a key component of cognitive function that impacts motor control. Hand movements such as grasping or reaching to grasp require the application of correct force and the coordination of multiple limb segments. Successful completion of hand motor task requires a certain degree of cognitive function to anticipate the requirement of the task. Cognitive function may thus be a confounding factor to rehabilitation outcomes. Objective This study aims to explore the impact of cognitive function on functional outcomes in people with subacute stroke after VR intervention. Methods Patients with stroke were first stratified into cognitively normal (CN) and cognitively impaired (CI), followed by allocation to the VR or control group (CG). Fugl-Meyer Assessment for Upper Extremity (FMA-UE), Barthel Index (BI), and Instrumental Activities of Daily Living (IADL) were recorded at baseline, 3 weeks after the intervention, and 3 and 6 months after the intervention. The between-group and within-group differences were assessed by repeated-measures analysis of variance (ANOVA). Results The between-group comparison indicated that FMA-UE, BI, and IADL (time effect P<.001 for all) scores improved significantly in both groups after the intervention. Repeated-measures ANOVA indicated that FMA-UE, BI, and IADL (time effect P<.001 for all) were significantly different in each subgroup after the intervention. For BI score, the ANOVA results showed obvious interaction effects (treatment × time × cognitive effect, P=.04). Conclusions VR intervention was as effective as traditional conventional therapy in improving upper limb function regardless of the cognitive functional level. Patients with stroke with impaired cognitive function may gain more improvement in upper limb function and independency in performing activities of daily living after a VR-based intervention. Trial Registration Chinese Clinical Trial Registry ChiCTR-IOC-15006064; https://tinyurl.com/4c9vkrrn

comparator, care providers, centers, and blinding status (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it) ii) Clarify the level of human involvement in the abstract, e.g., use phrases like "fully automated" vs. "therapist/nurse/care provider/physician-assisted" (mention number and expertise of providers involved, if any). (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it) iii) Open vs. closed, web-based (self-assessment) vs. face-to-face assessments in abstract: Mention how participants were recruited (online vs. offline), e.g., from an open access website or from a clinic or a closed online user group (closed usergroup trial), and clarify if this was a purely web-based trial, or there were face-to-face components (as part of the intervention or for assessment). Clearly say if outcomes were selfassessed through questionnaires (as common in web-based trials). Note: In traditional offline trials, an open trial (open-label trial) is a type of clinical trial in which both the researchers and participants know which treatment is being administered. To avoid confusion, use "blinded" or "unblinded" to indicated the level of blinding instead of "open", as "open" in web-based trials usually refers to "open access" (i.e. participants can self-enrol) (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it) iv) Results in abstract must contain use data: Report number of participants enrolled/assessed in each group, the use/uptake of the intervention (e.g., attrition/adherence metrics, use over time, number of logins etc.), in addition to primary/secondary outcomes. (Note: Only report in the abstract what the main paper is reporting. If this information is missing from the main body of text, consider adding it) v) Conclusions/Discussions in abstract for negative trials: Discuss the primary outcome -if the trial is negative (primary outcome not changed), and the intervention was not used, discuss whether negative results are attributable to lack of uptake and discuss reasons.

Background and objectives
2a Scientific background and explanation of rationale i) Describe the problem and the type of system/solution that is object of the study: intended as stand-alone intervention vs. incorporated in broader health care program? [1] Intended for a particular patient population? [1] Goals of the intervention, e.g., being more cost-effective to other interventions [1], replace or complement other solutions? (Note: Details about the intervention are provided in "Methods" under 5) ii) Scientific background, rationale: What is known about the (type of) system that is the object of the study (be sure to discuss the use of similar systems for other conditions/diagnoses, if appropriate), motivation for the study, i.e., what are the reasons for and what is the context for this specific study, from which stakeholder viewpoint is the study performed, potential impact of findings [2]. Briefly justify the choice of the comparator.   [6] used to design them (instructional strategy [1], behaviour change techniques, persuasive features, etc., see e.g., [7,8] for terminology). This includes an in-depth description of the content (including where it is coming from and who developed it) [1], "whether [and how] it is tailored to individual circumstances and allows users to track their progress and receive feedback" [6]. This also includes a description of communication delivery channels andif computer-mediated communication is a componentwhether communication was synchronous or asynchronous [6]. It also includes information on presentation strategies [1], including page design principles, average amount of text on pages, presence of hyperlinks to other resources etc. [1]. ix) Describe use parameters (e.g., intended "doses" and optimal timing for use) [1]. Clarify what instructions or recommendations were given to the user, e.g., regarding timing, frequency, heaviness of use [1], if any, or was the intervention used ad libitum.
Essential 8 x) Clarify the level of human involvement (care providers or health professionals, also technical assistance) in the e-intervention or as cointervention. Detail number and expertise of professionals involved, if any, as well as "type of assistance offered, the timing and frequency of the support, how it is initiated, and the medium by which the assistance is delivered" [6].  [1], as ehealth intervention may not be designed as standalone intervention. This includes training sessions and support [1]. It may be necessary to distinguish between the level of training required for the trial, and the level of training for a routine application outside of a RCT setting (discuss under item 21generalizability. i) If outcomes were obtained through online questionnaires, describe if they were validated for online use [6] and apply CHERRIES items to describe how the questionnaires were designed/deployed [9]. No EHEALTH-specific additions here i) Specify who was blinded, and who wasn't. Usually, in web-based trials it is not possible to blind the participants [1,3] (this should be clearly acknowledged), but it may be possible to blind outcome assessors, those doing data analysis or those administering co-interventions (if any).  [6] for some items to be included in informed consent documents. iii) Safety and security procedures, incl. privacy considerations, and "any steps taken to reduce the likelihood or detection of harm (e.g., education and training, availability of a hotline)" [1]. 6

RESULTS
Participant flow (a diagram is strongly recommended) 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome NPT: The number of care providers or centers performing the intervention in each group and the number of patients treated by each care provider in each center No EHEALTH-specific additions here 9 i) Strongly recommended: An attrition diagram (e.g., proportion of participants still logging in or using the intervention/comparator in each group plotted over time, similar to a survival curve) [5] or other figures or tables demonstrating usage/dose/engagement. i) Indicate if critical "secular events" [1] fell into the study period, e.g., significant changes in Internet resources available or "changes in computer hardware or Internet delivery resources" [1].
No EHEALTH-specific additions here i) In ehealth trials it is particularly important to report demographics associated with digital divide issues, such as age, education, gender, social-economic status, computer/Internet/ehealth literacy of the participants, if known. 17a For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) i) Report multiple "denominators" and provide definitions: Report N's (and effect sizes) "across a range of study participation [and use] thresholds" [1], e.g., N exposed, N consented, N used more than x times, N used more than y weeks, N participants "used" the intervention/comparator at specific pre-defined time points of interest (in absolute and relative numbers per group). Always clearly define "use" of the intervention. ii) Primary analysis should be intent-to-treat; secondary analyses could include comparing only "users", with the appropriate caveats that this is no longer a randomized sample (see 18-i).
i) In addition to primary/secondary (clinical) outcomes, the presentation of process outcomes such as metrics of use and intensity of use (dose, exposure) and their operational definitions is critical. This does not only refer to metrics of attrition (13-b) (often a binary variable), but also to more continuous exposure metrics such as "average session length". These must be accompanied by a technical description how a

Ancillary analyses
17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory No EHEALTH-specific additions here i) A subgroup analysis of comparing only users is not uncommon in ehealth trials, but if done it must be stressed that this is a self-selected sample and no longer an unbiased sample from a randomized trial (see 16-iii).

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Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) i) Include privacy breaches, technical problems. This does not only include physical "harm" to participants, but also incidents such as perceived or real privacy breaches [1], technical problems, and other unexpected/unintended incidents. "Unintended effects" also includes unintended positive effects [2].
ii) Include qualitative feedback from participants or observations from staff/researchers, if available, on strengths and shortcomings of the application, especially if they point to unintended/unexpected effects or uses. This includes (if available) reasons for why people did or did not use the application as intended by the developers.

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comparator, lack of or partial blinding, and unequal expertise of care providers or centers in each group ii) Highlight unanswered new questions, suggest future research [2]. 18 DISCUSSION Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses i) Typical limitations in ehealth trials: Participants in ehealth trials are rarely blinded. Ehealth trials often look at a multiplicity of outcomes, increasing risk for a Type I error. Discuss biases due to non-use of the intervention/usability issues, biases through informed consent procedures, unexpected events.
Generalisability 21 Generalisability (external validity, applicability) of the trial findings NPT: External validity of the trial findings according to the intervention, comparators, patients, and care providers or centers involved in the trial i) Generalizability to other populations: In particular, discuss generalizability to a general Internet population, outside of a RCT setting, and general patient population, including applicability of the study results for other organizations [2].
ii) Discuss if there were elements in the RCT that would be different in a routine application setting (e.g., prompts/reminders, more human involvement, training sessions or other co-interventions) and what impact the omission of these elements could have on use, adoption, or outcomes if the intervention is applied outside of a RCT setting. i) In addition to the usual declaration of interests (financial or otherwise), also state the "relation of the study team towards the system being evaluated" [2], i.e., state if the authors/evaluators are distinct from or identical with the developers/sponsors of the intervention.