The patient-reported impact of Charcot-Marie-Tooth disease in the real world: the design and conduct of a digital lifestyle study (CMT&Me)

Charcot-Marie-Tooth disease (CMT) is a rare, chronic, progressive motor and sensory neuropathy that affects the peripheral nervous system, leading to progressive, predominantly distal muscle weakness, atrophy, sensory loss and progressive limb dysfunction. As with many rare diseases, there is a lack of patient-reported data with which to understand and address patient needs. This study aims to explore the real-world impact of CMT from the patient perspective.

exibility, combined with occupational therapy, orthotics, pain management and psychological and social support (5). Surgical intervention may be required for more severe forms of the disease.
As with many other rare conditions, there is a lack of data about the burden of CMT with which to make informed decisions to improve disease management and outcomes. In particular, little evidence has been collected directly from people who have the condition, nor has much data been gathered in the real-world setting.
Patient reports often provide unique perspectives and in-depth depictions of disease burden and the impact of treatment. Thus, the role of patient-reported outcome (PRO) data is becoming increasingly recognized in strengthening disease understanding, and in the development, regulatory approval, use and reimbursement of treatments. To date, much PRO evidence has been generated in the clinical trial setting, with little data collected from patients being managed in real-world clinical practice. Real-world evidence (RWE) can provide more granular, longer-term data, from a broader patient population, than is typical in clinical trials, so there is clear value in its collection and analysis. In rare diseases like CMT, where there are likely to be challenges in conducting adequately sized and controlled clinical trials, RWE is of particular worth.
A growing recognition that RWE has a complementary value to randomized controlled trial evidence has been matched in recent years by regulators and health technology assessment (HTA) agencies publishing guidance for use of RWE. RWE is valued by regulators as a basis for regulatory decision-making, including approval of new indications for licensed drugs, as seen in the 21st Century Cures Act (6) and European Medicines Agency adaptive pathways (7). RWE is also accepted by many HTA agencies (e.g., the National Institute for Health and Care Excellence, and the Canadian Agency for Drugs and Technologies in Health) and payers in HTA submissions; including for orphan drugs (8).
There is a current need for a real-world study to explore the burden of CMT -a study that collects data directly from patients, about their experiences of living with, and managing, their condition.
The objective of this study, which is currently in the data collection phase, is to provide a detailed view of the impact of CMT and its treatment on patients in the real-world setting, including factors such as epidemiology, natural history, and clinical, humanistic and economic burden.

Results
Not applicable.

Discussion
CMT is a rare chronic disease and little is known about the burden it imposes on patients, their caregivers, and society. There is a lack of data collected in the real-world setting, directly from people who have the condition. Digital tools that enable real-time data reporting open up possibilities of publishing and acting upon the data faster, which is important to those affected by the disease. They are also useful for capturing data during periods of reduced patient access to clinics (e.g., the COVID-19 pandemic).
This international, longitudinal, real-world digital PRO study explores the burden of CMT experienced by patients. The study provides a detailed view of the impact of CMT and its treatment on patients in the real-world setting, including factors such as epidemiology, natural history, and humanistic and economic burden. Close and collaborative partnerships with CMT PAGs, who are 'experts by experience', will not only aid participant recruitment but also ensure true patient centricity of the research.
As requesting clinical con rmation of diagnosis is either onerous or possible to circumvent, participants are eligible for this study based on self-reported CMT diagnosis alone. While this means responses to questions within the study are therefore subject to error due to misinformation bias, data will be monitored on an ongoing basis for outliers -and ltered accordingly -to mitigate. Linkage studies (i.e., with existing registries of known CMT patients) also offer a powerful way of addressing the potential for error -the informed consent includes an opt-in to facilitate such studies. The risk of recruiting false patients in the rst place is very limited, however, given that the main method of recruitment is through CMT patient advocacy group networks.

Conclusion
In conclusion, this international, longitudinal, real-world digital PRO study -the rst of its kind -will undoubtedly help researchers and clinicians to understand the real-world impact of CMT and the unmet needs of patients.

Trial design
This is a prospective, real-world, patient-reported lifestyle study. Adults with CMT use a smartphone app, CMT&Me (Vitaccess Ltd; Oxford, UK), to enter regular data about CMT, its management, and its impact on their lives, over a period of at least two years.

Study setting
Participation is entirely via the CMT&Me app. There are no physical study sites. Data is collected from participants in the following countries: France, Germany, Italy, Spain, the UK, and the USA.

Eligibility criteria
Inclusion criteria are as follows: adult (age >18 years) diagnosed with CMT (self-reported diagnosis only) resident in one of the study countries willing to use their own smartphone/tablet willing to provide informed consent There are no speci c exclusion criteria.

Informed consent
Participants enrol and provide informed consent via the CMT&Me app. Participant brie ng materials are presented in a series of pages on the app, each followed by an informed consent statement relating to that section. Participants who agree to all the statements are considered to have given informed consent.
Consent includes agreement to the possibility of data being cross-referenced with other medical databases.

Risks
As this is a non-interventional study, participants are not expected to be at risk of physical harm.
Participation may trigger negative feelings in some participants. Participants are able to contact the research team if they have concerns or questions and are advised to contact their medical team where necessary.

Outcomes
As the aim of the study is to provide a detailed view of the impact of CMT on patients in the real-world setting, we are aiming to collect as much data as possible. Outcomes are therefore broad, with few prede ned analysis metrics.
Outcomes are as follows:

Sample size
We aim to enrol approximately 2,000 participants. A formal sample size calculation has not been performed as hypothesis testing is not planned and analysis is descriptive in nature.

Recruitment
Recruitment is community based, with potential participants made aware of the study via direct communication from CMT patient advocacy groups (PAGs), PAG and Vitaccess Ltd (CMT&Me app developer and study contract research organization) social media accounts, and word of mouth, including via PAG community networks and patient ambassadors. Would-be participants are able to download the CMT&Me app from Apple's App Store or Google Play, but study registration is contingent on meeting eligibility criteria.
The app was launched sequentially across the study countries in the following stages:

Data collection and management
Participants are asked to complete a pro le shortly after enrolment, which includes data on demographics, lifestyle characteristics, diagnosis and treatments, many of which are expected to remain fairly stable over the duration of the study. For those data that may change over the duration of the study (e.g., treatments, healthcare visits), participants are able -and encouraged -to add, edit or remove them.
Participants are also asked to complete a number of PRO instruments -after enrolment and then either monthly (EQ-5D-5L, BFI, PROMIS™ Pain Intensity 3a and Interference 6b, bespoke questionnaires for the study, PROMIS™ Sleep Disturbance 8a) or quarterly (WLQ, FES-I, LEFS, QuickDASH) -that assess HRQoL, speci c symptoms, and function. Summary descriptions of all PRO instruments are provided below. EQ-5D-5L The EQ-5D-5L comprises two parts: the EQ-5D-5L descriptive system and the EQ Visual Analogue Scale (EQ-VAS) (9).
The descriptive system comprises ve dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with ve levels (no problems, slight problems, moderate problems, severe problems, and extreme problems -i.e., higher scores represent worse health). The scores for the ve dimensions are combined in a ve-digit number describing the participant's health state.
The EQ-VAS records the participant's self-rated health on a vertical, visual analogue scale with endpoints labelled "the best health you can imagine" and "the worst health you can imagine". Higher scores represent better self-perceived health.

BFI
The BFI assesses participants' fatigue severity (10). The measure uses a 10-point numeric rating scale, and a recall period of 24 hours. A global fatigue score is calculated by averaging all nine items.

PROMIS™ Pain Intensity 3a and Interference 6b
The PROMIS™ Pain Intensity 3a includes two items that assess pain intensity over the last seven days (average and worst pain), and one for pain intensity "right now"; each scores using a ve-point scale (11).
Possible scores range from 2 to 10 where higher scores represent worst pain. This measure is generic rather than disease-speci c.
The PROMIS™ Pain Interference 6b assesses the extent to which pain hinders engagement with social, cognitive, emotional, physical and recreational activities, sleep, and enjoyment in life over the last seven days using a ve-point scale (12). Possible scores range from 6 to 30 where higher scores represent greater interference. This measure is generic rather than disease-speci c.
Bespoke questionnaires for this study Two cramp-speci c items were developed for inclusion in the study, measuring cramp frequency and intensity. The cramp frequency item asks, "In the past 7 days, how many days did you experience cramp?" and has ve possible response options: had no cramp, 1-2 days, 3-4 days, 5-6 days, every day. The cramp intensity item asks, "In the past 7 days, how intense was your cramp at its worst?" and has ve possible response options: had no cramp, mild, moderate, severe, very severe. Higher scores on both items represent greater cramp frequency and intensity respectively.

WLQ
The WLQ measures the impact of CMT on participants' work ability and productivity across four domains: time management, physical demands, mental-interpersonal demands, and output demands (13). Possible domain scores range from 0 to 100 and the recall period is the previous two weeks. WLQ domain scores will be converted into an estimate of productivity loss using an algorithm.

PROMIS™ Sleep Disturbance 8a
The PROMIS™ Sleep Disturbance 8a assesses self-reported perceptions of sleep quality, sleep depth, and restoration associated with sleep over the last seven days using a ve-point scale (14). Possible scores range from 8 to 40 where higher scores represent worse sleep disturbance. This measure is generic rather than disease-speci c.

FES-I
The FES-I measures the level of concern about falling during social and physical activities inside and outside the home, whether or not the person actually carries out the activity (15). The "usual" level of concern is measured on a four-point Likert scale (1 = not at all concerned to 4 = very concerned), with participants asked to consider how they usually carry out the activity. Possible scores range from 16 to 64 where higher scores represent greater concern about falling.

LEFS
The LEFS evaluates di culties because of lower limb problems in 20 activities, including work/school activities, hobbies, moving around the home, dressing, lifting, standing, sitting, walking, and running (16). The level of di culty is assessed for "today" using a ve-point Likert scale (0 = extreme di culty or unable to perform activity; 5 = no di culty). Lower scores represent greater di culties experienced because of lower limb problems.

QuickDASH
The QuickDASH measure uses 11 items to gauge physical function and symptoms in people with any or multiple musculoskeletal disorders of the upper limb (17). All questions are rated 1 to 5 (no di culty/none/not at all through to unable/extreme di culty). Possible scores range from 11 to 55 where higher scores represent greater di culties with physical function and symptoms.
Plans to promote participant retention and complete follow-up If, at any study time point, participants do not complete data entry for a certain section of their pro le or a PRO instrument within a one-week window, their data will be considered missing for that time point. They will still be able to enter data again at later required time points.
To promote engagement with the study app and continued data entry, participants will receive in-app messages, encouraging them to complete required data entry, thanking them for doing so, and stressing the importance of their contributions to research. Participants will also receive information about the study, updates on its progression, and emerging results via the study app, social media, and regular email newsletters.
CMT&Me also contains non-study features that are designed to help participants learn about or track their condition.

Data management
To promote data quality, rules were set for question responses (e.g., range limits for continuous variables, minimization of free-text data elds, limits to number of response options that can be selected). Data will also be checked and cleaned before analysis.
Each participant will log in to CMT&Me using unique self-generated login credentials, which are unknown and inaccessible to the study team. Data saved by participants in CMT&Me will be transferred to a central database, then aggregated and de-identi ed, as soon as is practicable. No personal data will be held on participants' devices. Personally identi able information (PII) will be encrypted with unique encryption keys at rest and all data will be encrypted in transit. All study data will be stored on a secure server.

Con dentiality
All PII will be protected by industry-standard methods, ensuring full con dentiality is maintained. PII is not held on participants' devices and cannot be viewed by the study sponsor or any external researchers who apply for access to the study data. Data will be stored in a central database in aggregated, de-identi ed form.

Statistical methods
Statistical methods for primary and secondary outcomes Data management and analysis will follow a pre-de ned statistical analysis plan. As this is an exploratory observational study, differences and patterns in the data will be analyzed, but without exploring causation. All analyses will be descriptive, and no hypotheses tested.
Aggregated de-identi ed data will be summarized as follows: For continuous variables, distributions: number, mean, standard deviation, median, minimum, maximum, 95% con dence interval For categorical variables, summaries: n, frequency and proportion For both variable types, the number and proportion of missing data will also be reported.
Descriptive distribution statistics for each PRO instrument score, or domain score, will be presented for baseline ( rst data entry timepoint) and at each time point thereafter, including at study end. Distribution statistics will also be generated to describe the outcomes at each time point for the absolute value and the calculated change from baseline.

Interim analyses
Interim analyses will be conducted upon registration of the 1,000 th participant and at 12-monthly intervals from study launch.
A nal analysis will be presented at study end (currently two years from study launch), based on data from all participants who have completed at least one PRO instrument, the necessary elements of their pro le, and have been enrolled in the study or have withdrawn.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data Missing data will be handled as set out in the scoring guidelines for the PRO instruments, and according to best practice for the pro le. All missing data will be assumed to be missing at random, and no adjustments will be made to account for missing data.
Plans to give access to the full protocol, participant-level data and statistical code Members of the public and external researchers can apply via the study website to be granted access to aggregated and anonymized study data. Access decisions will be granted under the purview of the study scienti c advisory board (SAB).

Oversight and monitoring
A key tenet of governance and monitoring is that the framework is transparent and public, and so accessible to would-be participants considering enrolling, as well as to enrolled participants. As such, all oversight and monitoring arrangements will be published on publicly available study webpages: https://vitaccess.com/cmt-and-me.
Composition of the data monitoring committee, its role and reporting structure An SAB was convened during the study design phase to protect participants' interest. The SAB is responsible for the following: Effective operational management of the study Ensuring that the study operates in the best interests of participants Ensuring that the study operates to the highest levels of academic rigor The SAB acts as an advisory/review body for the following: The SAB also acts as a decision-making body for third party data access requests.
In line with good practice recommendations (18), the SAB comprises independent clinical and PAG representatives from each study country, plus sponsor and Vitaccess representatives. The SAB will meet in person at least annually (where feasible), and by teleconference at least every six months.

Adverse event reporting and harms
There is no obligation to report adverse events recorded by participants. Participants who report receiving the sponsor's product PXT3003 (or other experimental drugs) would have already been enrolled in clinical trials, and it is assumed they would therefore be followed up under the relevant adverse event-reporting pathways.

Frequency and plans for auditing study conduct
The SAB will audit the study conduct on an ongoing basis.

Plans for communicating important protocol amendments to relevant parties
The study team will be responsible for communicating protocol amendments to relevant parties as necessary and must be approved by the SAB.