Expanded Disability Status Scale (EDSS) score is composed of the overall impression and individual scores of the following functional systems: cognition, mood, fatigue, vision, brain stem, upper extremities, lower extremities, bladder-intestinal function, sexuality. Scores are on a scale of 0 (healthy) to 10 (death from MS) with 0.5 unit increments

EDSS trend is measured by differentiating patients who stabilize from those who experience an increase of EDSS score (increment of ≥1 or ≥0.5 point if baseline EDSS was ≤5.0 or ˃5.0, respectively). Moreover, patients with progression will be categorized as patients with continuous disability accrual (CDA) or one-step worsening (OneS-wors), defined as:

• OneS-wors: the occurrence of one single episode of confirmed EDSS deterioration.
• CDA: occurrence of at least two episodes of OneS-wors associated with continuous disability progression between at least two time points.

NEDA-3 is defined as no Confirmed disability progression (CDP), no confirmed relapse and absence of T1 gadolinium-enhancing (Gd+) lesions.

The UKNDS is a questionnaire for recording impairments in MS from the patient's perspective and considers 12 functional systems: perception and thinking, mood, vision, speech and communication, swallowing, arm and hand function, walking ability, bladder function, bowel function, fatigue, sexuality, pain, cramps and others. Answering the questions results in a score of 0 (no disability) to 60 (maximum disability). This questionnaire will be completed by the patients during site visits.

The FSMC is a patient questionnaire for the clarification of cognitive and motor fatigue, a typical symptom of MS (Penner et al., 2009), and considers a cognitive, motor and total score. Score ranges from 200 to 100, the greater the score the greater the impairment caused by fatigue.

The HADS has seven items each for depression and anxiety subscales. Scoring for each item ranges from zero to three, with three denoting highest anxiety or depression level. A total subscale score of >8 points out of a possible 21 denotes considerable symptoms of anxiety or depression.

Calculations of scores: each of the 14 items is rated on a 4-point scale ('Yes, definitely', 'Yes, sometimes', 'No, not much' and 'No, not at all'). All items except 7 and 10 are scored as 'Yes, definitely' = 3 to 'No, not at all' = 0. Items 7 and 10 are scored as 'Yes, definitely' = 0 to 'No, not at all' = 3. The HADS consists of two sub-scores: the HAD-A for anxiety and HAD-D for depression; each sub-score ranges from 0 to 21 points; scores ≥11 indicate the presence of anxious or depressive disorders; scores between 8-10 points are borderline abnormal, and scores of ≤7 indicate that the disorder is not present.

The SDMT is a sensitive and specific test to investigate attention, concentration and information processing speed, which are typically impaired in cognitively impaired MS patients.

Nine numbers are shown paired with 9 corresponding individual symbols. Below this are further lines with symbols and empty boxes. The patients must assign the correct numbers to the symbols as quickly as possible. The number of correctly assigned numbers within 90 seconds gives the test score. The total duration of the test is about 5 minutes and scores range between 0 and 110 where higher scores indicate better result.

A deterioration of the SDMT score by ≥4 points is considered clinically relevant

The CGI scale represents a short, independent assessment by the treating physician of the overall condition of the patient.

It incorporates patient history, psychosocial circumstances, symptoms, behavior and the influence of symptoms on the patient's functional ability. The CGI consists of three different global measures and all three will be evaluated: Severity of illness (CGI-S) ranges from 0 to 7, Global Improvement (CGI-I) ranges from 0 to 7 and Efficacy index (CGI-E) ranges from 0 to 16. A higher score means a severe impact on the disease.

Number of relapse, number of relapse that affects the daily activities, number of relapse that required an hospitalization and number of treated relapse to be collected

Number of patients with presence of symptoms to be collected

The T25-FW is an objective and quantitative test of the lower extremities. The time in seconds it takes a patient to walk a distance of 25 feet (7.62 m) is measured. The patient should walk as quickly and safely as possible. This test is performed twice in a row and the mean value of the time required is documented in seconds. An improvement or deterioration of 20% is considered a significant change

This test examines manual dexterity. Patients must individually remove nine pegs from a flat dish with one hand and insert them into corresponding holes in a test board. The pegs are then placed back into the dish with the same hand. Two rounds are performed per hand and the average value of the time required is documented in seconds

The EQ-5D is a generic multidimensional measurement tool for describing health-related quality of life (EuroQol, 1999). The five domains of mobility, self-care ability, daily activities, pain/discomfort and anxiety/depression are considered. For each of the dimensions, the most appropriate answer from three given possibilities is selected (1=no problem, 2=moderate problem, 3=large problem). In addition, the patient marks the current state of health on a scale from 0 (worst conceivable state of health) to 100 (best conceivable state of health).

The TSQM-9 is a questionnaire to assess patient satisfaction with siponimod treatment. The TSQM-9 is a sound and valid measure of the major dimensions of patients' satisfaction with medication and also a good predictor of adherence across different types of medication and patient population.

Effectiveness, side effects, simplicity and overall satisfaction are all rated between 0 and 100. Higher values mean a worse condition. Responses to items are summed and transformed so that higher scores indicate greater satisfaction. Specifically, TSQM-9 scale scores are computed by adding the items loading on each domain. The lowest possible score is subtracted from the composite score and divided by the greatest possible score range. This provides a transformed score between 0 and 1 that is then multiplied by 100. If more than one item is missing from a subscale of the TSQM-9 for a particular patient, this subscale should be considered invalid for that respondent.

Exposure adjusted proportion of patients with adverse event (AE) or serious adverse event (SAE) per 100 subject-years to be collected

Discontinuation rates due to AE or other reasons to be collected

Proportion of patient who required first dose observation (FDO) when starting siponimod and the reason why