Cognitive training – HappyNeuron Platform.

All patients will follow a 12-week online cognitive training program using the HappyNeuron PRESCO® online platform, with (experimental group) or without (active control group) remote supervision by a neuropsychologist. Cognitive training will begin within 3 weeks of inclusion.

The HappyNeuron PRESCO® software offers a standardized intervention targeting several cognitive domains that are impaired with CRCI: memory, executive functions, attention, information processing speed, language, ect. The cognitive training includes 38 exercises and 9 levels of difficulty, with an easy-to-use interface and a fun format to keep patients motivated. The difficulty level of the training will increase based on the patient’s performance. Patients will be notified by email three times a week that their 20-minute training session is ready. Patients in the experimental group will not have access to the platform outside of their scheduled training sessions, while patients in the active control group will have free access to the platform during the 12-week of the program.

Remote supervision of cognitive training.

Patients randomized to the experimental group will be contacted by a neuropsychologist via videoconference once a week for a 30-minute supervision session during the 12-week program. After an initial semi-structured interview aimed at identifying domains of cognitive complaints, each session will be structured around individual, professional, or personal development goals: the neuropsychologist will review patient’s difficulties during the week and discuss their strengths and vulnerabilities with them. Supervision sessions will include 15 minutes of psychoeducation on brain, cancer and cognition (CRCI, episodic memory, working memory, attention and processing speed, executive function), and the neuropsychologist will also suggest cognitive strategies to improve the patient’s performance, address difficulties encountered with the online training platform, and provide compensatory strategies to use in everyday life. This educational content has been developed by the team of neuropsychologists of the “Cancer and cognition” platform (Inserm U1086) at the Comprehensive Cancer Center of Caen (France), based on the methodology of Schuurs and Green [35] and the content of cognitive workshops already organized internally in the Oncology Supportive Care Department.

Screening of eligible patients.

Patients will be screened based on their cognitive complaints and its impact on their quality of life, using the QoL subscale of the FACT-Cog questionnaire [30] based on normative data [31]); and based on the assessment of their cognitive status (using the MoCA cognitive screening test).

Pre-randomization assessments.

Patients wha have given their written informed consent will be assessed on site prior to randomization for the parameters considered for stratification:

• level of fatigue, using the FACIT-F [33],
• level of anxiety and depression, using the HADS [34],
• current physical activity (including participation in an adapted physical activity (APA) program), using a self-reported level of physical activity on a visual analog scale: low (VAS 0 to 3), moderate (VAS 4 to 6), high (VAS 7 to 10).

Assessments.

The study includes four assessment sessions: at baseline, before the start of the intervention (T0), at the end of the intervention (T1), then 3 months (T2) and 9 months (T3) after the end of the intervention. The assessments will include (Table 1):

• Medical information, such as cancer characteristics and treatments, as well as comorbidities from medical records, and sociodemographic information (age, education level, ect), at T0,
• Completion of Patient Reported Outcomes (PRO) self-report questionnaires to assess:
  • cognitive complaints, using the FACT-Cog [30], at T0, T1, T2, and T3,
  • quality of life, using the Functional Assessment of Cancer Therapy – General: FACT-G questionnaire [36] and the five-level measure of health status EQ-5D-5L [37], at T0, T1, T2, and T3,
  • sleep quality, using the self-report Insomnia Severity Index: ISI [38], at T0, T1, T2, and T3,
  • fatigue level, using the FACIT-F [33], and anxiety and depression level, using the HADS [34], at T0 (if more than one week after the pre-randomization assessment), T1, T2, and T3,
  • level of physical activity, using the International Physical Activity Questionnaire (IPAQ) [39], at T0, T1, T2, and T3,
• Assessment of objective cognitive functions, using the self-administered CNS Vital Signs® cognitive testing battery, at T0, T1, T2, and T3,
• A questionnaire assessing patient’s working situation (return to work, conditions of return to work: full or part-time, worplaces accomodations, professional retraining, ect), at T0, T1, T2, and T3,
• Biological assessments, at T0, T1, T2, and T3, including hematology (complete blood count, platelets, hemoglobin), C-reactive protein, serum biochemistry (sodium, potassium, chloride, calcium, creatinine, glucose, ferritin), and thyroid-function test (Thyroid-Stimulating Hormone (TSH)). An additional optional biological blood sample (6 tubes of 5 ml) will taken for future analysis at T0 and T1.
• At the end of the 12-week intervention (T1), patients will be asked to assess their satisfaction with the intervention using a questionnaire specific to each intervention group.

Medico-economic study.

We will conduct a within-study cost-utility analysis using standard methods, comparing online cognitive training supervised by a neuropsychologist with an unsupervised open-access online cognitive training program from a societal perspective. The results will be presented in terms of quality-adjusted life years (QALYs) and cumulative costs, not discounted due to the one-year time horizon (3 months intervention + 9 months follow-up). We will estimate the costs of all healthcare used in both groups, including:

• Labor costs for the supervised cognitive training,
• Physician services,
• Hospitalizations and emergency room visits,
• Outpatient diagnostic tests,
• Drugs, including the use of psychotropic medications,
• Home health care,
• Health-related out-of-pocket expenses and productivity costs.

The medico-economic evaluation will be based on national hospital admission costs, social health insurance service costs, and drug purchase prices. Productivity losses will be assessed by the mean gross domestic product (GDP) per capita. Healthcare costs will be compared between supervised and unsupervised groups for the period concerned, based on healthcare utilization data collected prospectively at the patient level using an electronic Case Report Form (eCRF) and hospital claims data. Overall quality of life assessed using the EQ-5D-5L will be used for the economic evaluation, to calculate QALYs. The cumulative costs and QALYs for each trial group will be estimated and compared in order to calculate the incremental cost-effectiveness ratio. Results will be expressed as incremental cost per QALYs. We will evaluate uncertainty and estimate confidence intervals around the estimates, using both deterministic and probabilistic methods. We will account for the correlation between costs and health outcomes using appropriate bivariate methods. Cost-effectiveness acceptability curves will be used to graphically represent the probability that the intervention is cost-effective for cost-effectiveness thresholds of €50 000 and €100 000 per QALY gained (multiple thresholds for sensitivity analyses). Reports will follow the Consolidated Health Economic Evaluation Reporting Standards.

Training of participating teams.

To ensure consistency across all participating centres, a comprehensive procedures manual will be prepared and approved by each centre prior to the start of the study. Study staff at each center will be trained on the consent process, eligibility screening, administering of the MoCA test (including training required for non-neuropsychologists), questionnaires, support for patients using the CNS vital Sign battery and the use of the HappyNeuron PRESCO platform.

Neuropsychological supervision.

In order to ensure consistent supervision, the neuropsychologist coordinator will thoroughly review a semi-structured interview questionnaire for the initial and follow-up interviews of patients in the experimental group, prior to the start of study. Weekly meetings will be held regurlarly to discuss patient progress and participation in the program, as required.

The educational content of these supervision sessions will be developed in advance and standardized among neuropsychologists involved in the project. This content will be based on the educational material already used by the neuropsychologists in the centre for cognitive workshops [35].

Protocol deviations.

A standard protocol deviations form will be used to track any deviations. The study staff will maintain the protocol deviations log. Study staff will also record deviations discovered during the data audit and reconcile errors.

Data monitoring and management.

The neuropsychologist coordinator will condust systematic monitoring of program adherence and patient improvements. Study staff will monitor data collection and protocol deviations. A data monitoring committee will not be necessary since the study is considered to be at minimal risk.

A Web-Based Data Capture (WBDC) system will be used for randomization, data collection and query handling. The investigator will ensure that data are recorded on the eCRFs as specified in the trial protocol and in accordance with the instructions provided. The investigator ensures the accuracy, completeness, and timeliness of the data recorded as well as of the provision of answers to data queries according to the Clinical Study Agreement. The investigator will be in charge of signature of the completed eCRFs. A copy of the completed eCRFs will be archived at the study site.