## Protocol Section
### Identification Module
**NCT ID:** NCT05376579

**Acronym:** ITASIA

**Brief Title:** Impact of Mayzent on aSPMS Patients in a Long-term NIS in Italy

**Official Title:** Impact of Mayzent (Siponimod) on Active Secondary Progressive Multiple Sclerosis Patients in a Long-term Non-interventional Study in Italy

#### Organization Study ID Info
**ID:** CBAF312AIT04
#### Organization
**Class:** INDUSTRY
**Full Name:** Novartis
### Status Module
#### Completion Date
**Date:** 2026-06-30

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2023-09-06

**Type:** ACTUAL

**Last Update Submit Date:** 2023-09-04

**Overall Status:** ACTIVE_NOT_RECRUITING

#### Primary Completion Date
**Date:** 2026-06-30

**Type:** ESTIMATED

#### Start Date
**Date:** 2022-06-17

**Type:** ACTUAL

**Status Verified Date:** 2023-09

#### Study First Post Date
**Date:** 2022-05-17
**Type:** ACTUAL
**Study First Submit Date:** 2022-05-12
**Study First Submit QC Date:** 2022-05-12
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** INDUSTRY

**Name:** Novartis Pharmaceuticals

#### Responsible Party

**Type:** SPONSOR

### Description Module

**Brief Summary:** This is an observational, multicenter, single-arm, prospective study conducted in Italy

**Detailed Description:** Primary data will be collected over a period of three years. Medical history of participants will be collected including EDSS, MRI outcomes, relapses and previous medication to allow the estimation of the effects of siponimod treatment on an individual basis.

### Conditions Module

**Conditions:**

- Active Secondary Progressive Multiple Sclerosis

**Keywords:**

- Secondary Progressive Multiple Sclerosis

- aSPMS

- NIS

- Italy

- Mayzent

- siponimod

### Design Module

#### Design Info

**Observational Model:** COHORT

**Time Perspective:** PROSPECTIVE

#### Enrollment Info

**Count:** 134

**Type:** ACTUAL

**Study Type:** OBSERVATIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** patients treated with siponimod

**Intervention Names:**

- Other: siponimod

**Label:** siponimod

### Interventions

#### Intervention 1

**Arm Group Labels:**

- siponimod

**Description:** Prospective observational cohort study. There is no treatment allocation. Patients will be invited to participate in the study after the independent decision by physician and patient to start siponimod treatment as routine clinical care.

**Name:** siponimod

**Other Names:**

- mayzent

**Type:** OTHER

### Outcomes Module

#### Primary Outcomes

**Description:** Confirmed disability progression (CDP) is defined as a ≥1.0-point worsening of Expanded Disability Status Scale (EDSS) score from ≤5.0 baseline or a 0.5-point worsening from \>5.0 baseline for at least 6 months OR a ≥4.0-point confirmed cognitive worsening (CCW) from baseline of Symbol Digit Modalities Test (SDMT) for at least 6 months.

**Measure:** Proportion of patients with six-month CDP during 36 months of treatment

**Time Frame:** 36 months

#### Secondary Outcomes

**Description:** ARR is the number of relapses during the period / person-years of subject Person-years for subject = period (in days) / 365.25

**Measure:** Annualized relapse rate (ARR)

**Time Frame:** Month 12, month 24 and month 36

**Description:** Number of new/newly enlarging T2-hyperintense lesions and number of new 1 gadolinium-enhancing (Gd+) lesions is collected

**Measure:** Number of new/newly enlarging T2 [neT2] and Gd+T1 lesions

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** 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

**Measure:** Expanded Disability Status Scale scores

**Time Frame:** Month 12, month 24 and month 36

**Description:** 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.

**Measure:** Expanded Disability Status Scale trend

**Time Frame:** Month 12, month 24 and month 36

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

**Measure:** Proportion of patients with No Evidence of Disease Activity (NEDA)-3

**Time Frame:** Month 12, month 24 and month 36

**Description:** 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.

**Measure:** UK Neurological Disability Scale (UKNDS)

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** 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.

**Measure:** Fatigue Scale for Motor and Cognitive Functions (FSMC)

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** 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.

**Measure:** Hospital Anxiety and Depression Scale (HADS)

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** 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

**Measure:** Symbol Digit Modality test (SDMT)

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** 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.

**Measure:** Clinical Global Impression (CGI)

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** 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

**Measure:** MS activity status (MS-AS) - number of relapse

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** Number of patients with presence of symptoms to be collected

**Measure:** MS activity status (MS-AS) - Number of patients with presence of symptoms

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** 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

**Measure:** T25-foot-walk

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** 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

**Measure:** 9-Hole peg test

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** 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).

**Measure:** EQ-5D: EuroQol five-dimensional

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

**Description:** 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.

**Measure:** TSQM-9: Treatment Satisfaction Questionnaire for Medication

**Time Frame:** Baseline, month 3, month 6, month 12, month 18, month 24, month 30 and month 36

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

**Measure:** Exposure adjusted proportion of patients with adverse event (AE) or serious adverse event (SAE) per 100 subject-years

**Time Frame:** Up to 36 months

**Description:** Discontinuation rates due to AE or other reasons to be collected

**Measure:** Discontinuation rates due to AE or other reasons

**Time Frame:** Up to 36 months

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

**Measure:** Proportion of patient who required FDO when starting siponimod and the reason why

**Time Frame:** Baseline

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Signed informed consent: patient must provide written informed consent before any study assessment is performed.
2. Male/female participants aged between 18 and 60.
3. Documented diagnosis of active SPMS.
4. Siponimod treatment as routine medical care: patients newly treated with siponimod (starting not more than 7 days before baseline visit), for whom the decision to start treatment has already been taken independently of study inclusion based on clinical practice and according to SmPC and AIFA criteria, and who successfully qualified for treatment with siponimod (i.e. passed the screening procedure mandated by the SmPC and Risk Management Plan (RMP) for this treatment, including genotyping for CYP2C9 to determine CYP2C9 metaboliser status).

Exclusion Criteria:

1. Patients treated outside the approved siponimod label or with any controindication indicated in the SmPC.
2. Pregnant or lactating women.
3. Patients with any clinical condition that may interfere with the subject's ability to cooperate and comply with the study procedures based on the investigator's judgement.
4. Current participation in an interventional trial.
5. Treatment with siponimod prior to inclusion in this study (siponimod can be started not more than 7 days before baseline visit).

**Maximum Age:** 60 Years

**Minimum Age:** 18 Years

**Sampling Method:** NON_PROBABILITY_SAMPLE

**Sex:** ALL

**Standard Ages:**

- ADULT

**Study Population:** patients in Italy with active SPMS treated with siponimod as per label and local clinical practice.

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Ancona

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** AN

**Zip:** 60126

**Location 2:**

**City:** L Aquila

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** AQ

**Zip:** 67100

**Location 3:**

**City:** Bergamo

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** BG

**Zip:** 24128

**Location 4:**

**City:** Bologna

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** BO

**Zip:** 40139

**Location 5:**

**City:** Brescia

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** BS

**Zip:** 25123

**Location 6:**

**City:** Como

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** CO

**Zip:** 22100

**Location 7:**

**City:** Catanzaro

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** CZ

**Zip:** 88100

**Location 8:**

**City:** Foggia

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** FG

**Zip:** 71100

**Location 9:**

**City:** Genova

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** GE

**Zip:** 16132

**Location 10:**

**City:** Messina

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** ME

**Zip:** 98121

**Location 11:**

**City:** Milano

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** MI

**Zip:** 20133

**Location 12:**

**City:** Palermo

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** PA

**Zip:** 90127

**Location 13:**

**City:** Padova

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** PD

**Zip:** 35128

**Location 14:**

**City:** Pisa

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** PI

**Zip:** 56126

**Location 15:**

**City:** Pavia

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** PV

**Zip:** 27100

**Location 16:**

**City:** Roma

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** RM

**Zip:** 00133

**Location 17:**

**City:** Roma

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** RM

**Zip:** 00152

**Location 18:**

**City:** Roma

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** RM

**Zip:** 00189

**Location 19:**

**City:** Orbassano

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** TO

**Zip:** 10043

**Location 20:**

**City:** Trieste

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** TS

**Zip:** 34149

**Location 21:**

**City:** Vicenza

**Country:** Italy

**Facility:** Novartis Investigative Site

**State:** VI

**Zip:** 36100

**Location 22:**

**City:** Napoli

**Country:** Italy

**Facility:** Novartis Investigative Site

**Zip:** 80132

**Location 23:**

**City:** Napoli

**Country:** Italy

**Facility:** Novartis Investigative Site

**Zip:** 80138

**Location 24:**

**City:** Novara

**Country:** Italy

**Facility:** Novartis Investigative Site

**Zip:** 28100

#### Overall Officials

**Official 1:**

**Affiliation:** Novartis Pharmaceuticals

**Name:** Novartis Pharmaceuticals

**Role:** STUDY_DIRECTOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000010335

- Term: Pathologic Processes

- ID: D000020278

- Term: Demyelinating Autoimmune Diseases, CNS

- ID: D000020274

- Term: Autoimmune Diseases of the Nervous System

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000003711

- Term: Demyelinating Diseases

- ID: D000001327

- Term: Autoimmune Diseases

- ID: D000007154

- Term: Immune System Diseases

- ID: D000009385

- Term: Neoplastic Processes

- ID: D000009369

- Term: Neoplasms

- ID: D000002908

- Term: Chronic Disease

- ID: D000020969

- Term: Disease Attributes

### Condition Browse Module - Browse Branches

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: BC20

- Name: Immune System Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M12060

- Name: Multiple Sclerosis

- Relevance: HIGH

- As Found: Multiple Sclerosis

- ID: M15415

- Name: Sclerosis

- Relevance: HIGH

- As Found: Sclerosis

- ID: M12307

- Name: Neoplasm Metastasis

- Relevance: HIGH

- As Found: Secondary

- ID: M22313

- Name: Multiple Sclerosis, Chronic Progressive

- Relevance: HIGH

- As Found: Secondary Progressive Multiple Sclerosis

- ID: M4629

- Name: Autoimmune Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M22098

- Name: Demyelinating Autoimmune Diseases, CNS

- Relevance: LOW

- As Found: Unknown

- ID: M22094

- Name: Autoimmune Diseases of the Nervous System

- Relevance: LOW

- As Found: Unknown

- ID: M6909

- Name: Demyelinating Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10200

- Name: Immune System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12330

- Name: Neoplastic Processes

- Relevance: LOW

- As Found: Unknown

- ID: M6147

- Name: Chronic Disease

- Relevance: LOW

- As Found: Unknown

- ID: M22700

- Name: Disease Attributes

- Relevance: LOW

- As Found: Unknown

- ID: T1303

- Name: Chronic Graft Versus Host Disease

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000009362

- Term: Neoplasm Metastasis

- ID: D000009103

- Term: Multiple Sclerosis

- ID: D000020528

- Term: Multiple Sclerosis, Chronic Progressive

- ID: D000012598

- Term: Sclerosis

### Intervention Browse Module - Ancestors

- ID: D000081243

- Term: Sphingosine 1 Phosphate Receptor Modulators

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000007166

- Term: Immunosuppressive Agents

- ID: D000007155

- Term: Immunologic Factors

- ID: D000045505

- Term: Physiological Effects of Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M271068

- Name: Siponimod

- Relevance: HIGH

- As Found: Noncontiguous stage II marginal zone lymphoma

- ID: M10212

- Name: Immunosuppressive Agents

- Relevance: LOW

- As Found: Unknown

- ID: M10201

- Name: Immunologic Factors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000578989

- Term: Siponimod

### Misc Info Module

- Version Holder: 2024-05-24
