Explanation for the choice of comparators 6b
The control group is a wait list control group with no dedicated intervention. After the baseline measurements, the study participants within the CG may follow their usual standard care such as occupational therapy, physiotherapy, or psychotherapy. This approach was chosen to mirror the prevailing therapeutic realities, considering that a substantial number of individuals with MCI remain untreated despite their diagnosis [44]. Subsequently, the control group will also be granted full access to NeuroNation MED after the intervention duration. Both the IG and CG will receive free access to the NeuroNation MED app for a year.
Intervention description 11a
The intervention includes 12 weeks of mobile adaptive and personalized cCT with NeuroNation MED. The individual exercises are performed within the NeuroNation MED app and are developed based on scientific training concepts to address the relevant cognitive domains. This entails defining the training program based on each participant’s cognitive profile and continuously adapting it according to their individual performance within the exercises. In the context of the app, the term “cognitive profile” does not refer to linking data to clinical assessments within the study, but rather to the use of in-app modules that aim to adjust the training plan and show the progress in the categories of the app. A cognitive profile is derived from relative strengths and weaknesses in the four cognitive domains defined by the NeuroNation MED app (i.e., psycho-motor speed, reasoning, attention, memory). Therefore, these in-app modules are aligned with the exercise design of the app. For the various performance assessments in the app, which form the basis of the personalization algorithm, reference values from the NeuroNation App database, which are available aggregated per age group/exercise within the app/in-app modules adjusting the training plan, are used. Furthermore, the NeuroNation MED app offers supplementary content (“NeuroBooster”) providing participants with the option to access 19 different resources on health literacy, performance enhancement, well-being, and relaxation. These resources feature graphical instructions with short animations to demonstrate the correct execution of the exercises.
Participants within the IG can choose from four intensity levels ranging from 25 to 40 min. Trial participants are recommended to undergo a 12-week training program, consisting of three training sessions per week. Each exercise has a net time of 90 s with the net time being the duration the exercise timer is active. However, training sessions can exceed 40 min due to the need for extra time required to work through explanatory texts, educational content, and user guidance.
Criteria for discontinuing or modifying allocated interventions 11b
Each participant of the study will be informed that participation is voluntary and that withdrawal from the study is possible at any time. It will be communicated that withdrawal will have no effect on possible further treatment at any participating institution. The study may be terminated before its intended completion if ethical concerns arise, if there is insufficient recruitment of participants, or if the safety of the participants is compromised or uncertain. Furthermore, termination may occur if changes in accepted clinical practices render it unwise to continue the clinical trial, or if early indications of harm from the intervention are observed.
Since the study follows an intention-to-treat approach, participants in the IG will not be prescribed a fixed amount of training time or session count for using the NeuroNation MED app. At the first appointment, the IG is instructed to adhere to a certain weekly usage duration and frequency of use, but this is not mandatory for study participation and may vary among participants during the intervention period.
Strategies to improve adherence to interventions 11c
In order to increase the adherence of the participants in the intervention group, various actions are implemented. Firstly, all participants in the IG receive a printed manual with instructions on how to use the NeuroNation MED app. This includes information on how to use the platform, troubleshooting solutions, contact persons, and recommended training duration and intensity. Additionally, the participants receive a weekly newsletter via an anonymous mailing list with tips on a healthy, active lifestyle, psychoeducational content regarding cognitive and brain plasticity, and motivational content. Exemplary topics of the 12 distinct newsletters are risk and protective factors of cognitive health, emotional well-being, the Mediterranean diet, physical activity, and social networks. After the first appointment, the participants of the IG receive an email containing their access credentials and helpful information about the NeuroNation MED app. Another follow-up email will be sent 1 week after t0, serving as a reminder and inquiring about any technical problems or if the training has commenced.
Relevant concomitant care permitted or prohibited during the trial 11d
Study participants in both study groups will be asked not to perform any other cCT program (other than the intervention) as part of their study participation. However, all participants were allowed to follow any other forms of therapy in the context of medical treatment (e.g., ergotherapy, medication, etc.) or private measures (sports, social activities, etc.). Rather, these should be documented by the participants of both the CG and IG in a patient diary, which should be continuously updated during the intervention period of 12 weeks.
Provisions for post-trial care 30
No direct relevant risks arise for the study participants from the implementation of the training units within the app or the study-related assessments or questionnaires. All participants will be granted complimentary 12-month access to the NeuroNation MED app upon completion of the study.
Outcomes 12
The primary endpoint of the study is the S-NAB adapted to German language [45, 46]. As a comprehensive test battery for neuropsychological assessment, the S-NAB is primarily used in clinical neuropsychology with adults aged 18 and older. The S-NAB combines 14 individual neuropsychological tasks and thus offers the possibility of gaining a diagnostic overview in a short time frame. The functional areas of attention, language, memory, perception, and executive functions are examined with at least two tasks each. Due to its short duration, the S-NAB module is well-suited for patients with limited resilience. Compared to other neuropsychological screenings, the tasks of the S-NAB are challenging enough to detect mild to moderate cognitive impairment [47]. Furthermore, the S-NAB is available in two parallel versions, which is a necessity for the pre-post design of the current study. The S-NAB offers norm scores covering the entire adult age range based on a representative sample from Germany. Additionally, the S-NAB has a mean score of 100 with a standard deviation of 15.
Several important psychosocial and health-related aspects were selected as secondary endpoints. Therefore, in the current study, the following constructs were recorded: psychological well-being, self-efficacy, depressive symptoms, and anxiety symptoms.
The Hamburg Modules for the Assessment of General Aspects of Psychosocial Health for Therapeutic Practice (HEALTH-49) is a self-report instrument for the multidimensional assessment of psychosocial health [48]. This instrument takes into account psychosocial aspects in therapy planning and diagnostics, as well as in quality assurance and the evaluation of psychotherapeutic and medical treatments in general. For the current study, the two modules Psychological Well-Being (5 questions) and Self-Efficacy (5 questions) of the HEALTH-49 were selected. Each module is rated on a Likert-type scale ranging from zero to four, with total scores that are averaged. Additionally, lower scores on both subscales are indicative of elevated levels of self-efficacy and general well-being.
The Hospital Anxiety and Depression Scale—German Version (HADS-D) is a medical psychological questionnaire and is used to assess anxiety and depressive symptoms in patients with physical illnesses or physical complaints [49,50,51]. The extent of anxious and depressive symptoms during the past week is assessed by means of self-report, which is recorded on two Likert-type subscales with seven items each that range from zero to three. Higher total scores on the subscales indicate higher levels of anxiety or depressive symptoms. The cumulative score of the two subscales provides a measure of general psychological impairment.
Especially in the context of neurological diseases, a significant measure of quality of life involves the subjective impairment resulting from the disease’s impact on cognitive failures in daily life. The Cognitive Failures Questionnaire—German Version (CFQ-D [52]) is a self-assessment questionnaire consisting of 32 Likert-type items. It evaluates the frequency of committed everyday errors in the past year across the domains of perception, memory, and action regulation [53, 54]. The items are scored on a scale from zero to four. By summing up all the item scores, the total score is derived, which serves as a measure of an individual’s inclination to make everyday errors. Higher total scores indicate a higher subjective probability of encountering everyday mistakes and cognitive lapses.
Health literacy and patient sovereignty are potential influencing factors on patient health, as higher competence and sovereignty in this area is associated with both higher treatment adherence and better preventive health behaviors [55]. Measurement of this aspect is crucial, serving as both a control variable to ensure comparability between the intervention and control groups, and as a means to detect potential positive effects of the intervention on this aspect. The Health Literacy Questionnaire—German Version (HLQ-G) [56, 57] was selected as the measurement instrument. The questionnaire comprises 44 questions distributed across nine domains, with each domain containing 4 to 6 questions. The domains capture (1) feeling understood and supported by health care providers, (2) having enough information to manage one’s own health, (3) actively doing something for one’s own health, (4) social support for one’s health, (5) evaluating health information, (6) ability to actively engage with health care providers, (7) navigating the healthcare system, (8) ability to find good health information, and (9) understand health information well enough to apply it. For the first five subscales, the scores range from 1 to 4, while for scale six to nine, the scores range from 1 to 5. Higher scores reflect higher health literacy. To obtain scores for each domain, the response to the questions are summed and averaged.
In order to analyze the usability of the NeuroNation MED app, the System Usability Scale (SUS) is used [58]. This is a widely used questionnaire developed to assess the usability of a system, product, or service. It consists of 10 items on a 5-point Likert scale that measures the user’s perception of various aspects of usability, such as ease of use, learnability, efficiency, and satisfaction. The SUS provides a standardized and reliable method to evaluate and compare the usability of different systems. The SUS score ranges from 0 to 100 and can be interpreted in many ways, e.g., by percentiles, grades, acceptability, adjectives, or the Net Promoter Score. The raw SUS values can be converted into percentile ranks. The average value at the 50th percentile is 68.
Moreover, usage data from study participants will be recorded for analysis. This includes documenting both the frequency of training days and the duration of app usage. To effectively account for potential confounding variables during the survey period and to evaluate the impact of external factors on participants’ cognitive status, participants will maintain a study diary throughout the 12-week duration. This diary aims to document activities that have the potential to influence cognitive status.
Exclusively at the test center of Jena University Hospital (JUH), further secondary outcome measures encompass visual attentional parameters based on the theory of visual attention [59], assessed in a whole report paradigm. In addition, clinical routine data relevant to post-COVID syndrome will be measured, such as questionnaires concerning fatigue (Brief Fatigue Inventory [60], Fatigue Assessment Scale [61]), psychological burden (Patient Health Questionnaire 9 [62], Beck Depression Inventory II [63], Post-Traumatic Stress Syndrome 14-Questions Inventory [64]), sleep/sleepiness (Pittsburgh Sleep Quality Index [65]; Epworth Sleepiness Scale [66]), cognition (Functional Assessment of Cancer Therapy—Cognitive Function [67]), and established neuropsychological tests (computerized Test of Attentional Performance—TAP [68]).
Participant timeline 13
The complete participant timeline is illustrated in Table 1.
Sample size 14
The assumed effect size is based on results of previous studies using the cognitive training program “NeuroNation BT” [69] and comparable digital cognitive training applications [25, 26, 36, 70]. A calculation by means of a t-test for independent samples was used as the basis for the sample size calculation within the trial described here. With an allocation ratio of 2:1, if 164 subjects are included in the IG and 82 subjects are included in the control group, differences with an effect size of 0.39 or greater can be shown (a priori power analysis, Wilcoxon-Mann–Whitney test (two groups), power = 80%, two tails significance level α = 0.05). This resulted in the total sample size of 246. We expect a drop-out rate of approximately 15% [71], which results in a sample size to be recruited of N = 286. This sample size calculation was performed with G*Power 3.1.
Recruitment 15
Potential participants are recruited via the volunteer database of the Geriatrics Research Group of the Charité—Universitätsmedizin Berlin, the Neuro-Post-COVID Center of the Department of Neurology of Jena University Hospital, the Department of Neurology of the University Hospital Cologne, the Clinic for Neurology with Experimental Neurology, Charité, and the Neuropsychological University Outpatient Clinic of the LMU Munich. At the Centre Hospitalier Neuro-Psychiatrique in Luxembourg, participants were recruited from the long-COVID consultation. Furthermore, (neuro-) rehabilitation clinics, psychotherapists in private practice, and various clinics of the Charité and the other participating study centers will be used as gatekeepers for recruitment and flyers will be distributed. In addition, announcements on intranet sites will be used, a newsletter will be sent to NeuroNation users, and outdoor and radio advertising will be used to draw attention to the study.
The planned study will include diagnosed patients with cognitive impairment (ICD-10-GM: F06.7). The study population will be recruited via the clinics of the study centers involved in the study and via external practices as multipliers, each of which is diagnosed as part of standard care. These clinics and practices will approach patients with diagnoses and characteristics matching the inclusion criteria for the planned survey. The multipliers receive flyers designed for the study that provide information on the inclusion and exclusion criteria applicable to this study. These also include, by way of example, the diagnosis relevant to this study. Thus, all potential study participants have a medically confirmed ICD-10-GM F06.7 diagnosis.
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