Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory disease of the central nervous system (CNS) which attacks myelinated axons, destroying, to varying degrees, both myelin and axonal tissue (1–3). The disorder, which affects an estimated 137,000 patients in Italy (4), typically presents between the ages of 20 and 45 years, being less frequent in childhood or late middle age (5). The cause of MS is unknown, but it appears to involve a combination of genetic susceptibility and non-genetic triggers, such as viral, metabolic, or environmental factors, that result in a self-sustaining autoimmune disorder which leads to recurrent immune attacks on the CNS (5–7).

The course of MS is highly varied and is often characterized initially by episodes of reversible neurological deficits that are followed by progressive neurological deterioration over time (8). Some patients experience a highly active disease course, with rapid and early-onset disability, heralded by high relapse rates and early motor, cerebellar and/or cognitive dysfunction (9). Highly active relapsing MS (RMS) is characterized by neurological deterioration causing motor and cognitive dysfunction that impacts health-related quality of life (HRQoL) (10). Despite the recent introduction of new disease-modifying therapies (DMTs) for treating MS (11–13), a substantial clinical burden remains, and new approaches are required to reduce the number of relapses and prevent disability progression, while maintaining QoL (14).

Cladribine is a synthetic deoxyadenosine analog prodrug that is activated through phosphorylation by deoxycytidine kinase that preferentially accumulates to cytotoxic levels in lymphocytes. This results in targeted and sustained reductions of the T and B lymphocytes implicated in MS pathogenesis (15). Cladribine tablets were approved for the treatment of highly active RMS in adults by the European Medicines Agency (EMA) in 2017 (16).

Two short courses of cladribine tablets across 2 consecutive years (cumulative dose 3.5 mg/kg) provides clinically and statistically significant benefits in patients across the RMS spectrum (early to late stages, treatment naïve, or experienced patients) (17, 18). Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. In the approved treatment regimen, these short treatment courses in years 1 and 2 are followed by 2 years without treatment (16).

Patients with MS frequently report limitations in daily activities due to fatigue, problems with balance or coordination, cognitive impairment, and sleep disturbances (19). In addition, MS has been associated with diminished QoL due to the limitations it may impose on employment and social activities (20, 21). Improving QoL is therefore an important goal in the treatment of MS and QoL assessment can help guide healthcare decisions toward this end (22).

Patient-reported outcomes (PROs) play an increasing role in MS research and practice and are essential toward understanding the effects of MS and its treatment on patients’ lives. For MS, the relevance of QoL as an overall subjective measure is underpinned by studies showing that increase in QoL during treatment is accompanied by improvement in fatigue, depression, or cognition (23). In the CLARITY trial, in addition to the observed reduction in relapse, disability progression, and Magnetic Resonance Imaging (MRI)-assessed disease activity compared with placebo, there was a significant improvement in EuroQoL 5-Dimension (EQ-5D) index scores and a trend toward improvement as measured via the Multiple Sclerosis Quality of Life-54 (MSQoL-54) Questionnaire (24). The ongoing open label, single-arm, Phase IV CLARIFY-MS trial (NCT03369665) expanded these findings, showing statistically significant improvements over 24 months in the physical and mental health composite scores of the MSQoL-54 (25).

Patient-reported outcome assessment is expected to have an increasing role in the future. Although it is important to evaluate traditional measures, e.g., relapse count and disability progression, such information alone is insufficient toward the comprehensive assessment of disease outcomes; instead, the use of PROs and QoL assessments that address the physical, psychosocial, and sexual aspects of the disease (26) should be undertaken. The application of tools such as the MSIS-29 (27) and the Patient-Reported Outcomes Measurement Information System (PROMIS) (28) can overcome the deficiencies of traditional assessments [e.g., the Expanded Disability Status Scale (EDSS) (29), and MRI findings] by capturing outcomes that are most important to MS patients in terms of improvement in daily life and experience (30).

The fluctuating nature of MS symptoms, fatigue during the course of the day or presence of relapse, for example, can make it difficult to obtain a representative measurement of a patient’s condition at a clinical visit. Toward this end, the use of wearable technology allows continuous monitoring of function during the patient’s normal daily routine (31, 32), thereby allowing their disease status to be measured and monitored over time (33).

Multiple sclerosis symptoms include motor impairment and gait disturbances (34, 35), and patients with MS have been found to be less physically active compared with the general population (36, 37). Mobility measures based on functional performance, physical assessment, and patient self-reporting, often have low sensitivity. Wearable devices with inertial measurement units help to overcome such limitations and can be used to evaluate functional capacity in real-world settings (38). These wearable activity trackers may be affected by gait disturbances in patients with advanced MS, be less accurate than professional instruments when measuring low activity levels (39), but they are suitable for estimating changes in intra-individual activity in patients with mild or moderate MS (40, 41).

There are several therapeutic options for treating RMS, and it is important to identify optimal sequencing, understand the patient journey through the various treatments, and generate evidence to inform therapy switches. In the pivotal CLARITY study [17], approximately one-third of patients had switched to cladribine after treatment with interferon-beta or glatiramer acetate; however, dimethyl fumarate and teriflunomide were not yet approved at that time.

The aim of this study will be to evaluate the effect of cladribine tablets on PROs and physical activity, and their correlation with disability, as well as the clinical effectiveness and tolerability of cladribine in patients with highly active RMS who are switching from a first-line MS DMT to cladribine tablets as their first second-line treatment in routine clinical practice. CLADFIT also aims to investigate the reasons for switching to cladribine and provide important information on washout strategies after first-line therapies. This data will be useful to inform therapeutic choices supported by scientific evidence. Quality of life, health utilization and treatment satisfaction data will also support pharmacoeconomic analyses.

This protocol complies with the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Checklist for Study Protocols (Revision 4). Trial Registration: European Union Electronic Register of Post-Authorisation Studies (EU PAS) number EUPAS43893.

CLADFIT will be subject to several limitations due to its design as an open-label, observational study. Patient assessments will be limited to standard-of-care protocols for study visits, imaging, and laboratory testing. This could result in inconsistent data collection, potentially leading to missing data, information bias, and residual confounding. Interpretation of the results may also be affected by treatment-related variability, such as adherence, discontinuation, or potential interactions with other medications. Additional limitations include potential biases from patient selection, loss to follow-up, and patient recall.

CLADFIT’s strengths include a prospective and longitudinal design, with clear enrolment goals based on the primary objective. Advantages also include a variety of validated outcome measures that assess a broad range of functional, clinical, cognitive, and psychological domains a distinct perspective on the patient experience and the impact of treatment on daily life. Several of the instruments in this study will have overlapping domains, so that psychological function assessed on 5 different instruments, and physical functions on 4 different instruments. Correlations among these results may provide insight into their consistency as a real-world study, CLADFIT will reflect everyday clinical practice more closely than randomized controlled trials by enrolling more representative patient populations and administering treatments that are characteristic of those experienced in routine clinical practice, making its findings useful for assessing and improving patient care.

GB: Writing – original draft, Writing – review & editing, Data curation, Investigation. CC: Writing – original draft, Writing – review & editing, Data curation, Investigation, Methodology, Validation. DM: Writing – original draft, Writing – review & editing, Data curation, Investigation. MM: Writing – original draft, Writing – review & editing, Data curation, Investigation. DP: Writing – original draft, Writing – review & editing, Data curation, Investigation. FA: Writing – original draft, Writing – review & editing, Conceptualization. SC: Writing – original draft, Writing – review & editing, Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation. FP: Writing – original draft, Writing – review & editing, Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation.