Real-world Experience of Oral Agents On Fatigability in Multiple Sclerosis

Официальное название

Real-World Comparative Effects of Teriflunomide and Dimethyl Fumarate on Physical and Cognitive Fatigability in Multiple Sclerosis: The ROOF-MS Multicenter Prospective Cohort Study

Обзор

This multicenter, prospective, real-world study evaluates how two commonly used oral disease-modifying therapies-teriflunomide and dimethyl fumarate-affect physical and cognitive fatigability in adults with multiple sclerosis (MS). Fatigability refers to an objective decline in physical or cognitive performance during sustained activity and represents a major barrier to daily functioning for many individuals with MS. Participants starting either teriflunomide or dimethyl fumarate as part of routine clinical care will be followed for 12 months at regular visits (baseline, 3, 6, 9, and 12 months). At each visit, standardized assessments will measure walking endurance, gait performance, hand function, and information-processing speed. Patient-reported outcomes about fatigue, mood, quality of life, and daily functioning will also be collected. Brain MRI scans performed as part of usual care will be reviewed to document disease activity. The goal of the ROOF-MS study is to understand whether these two therapies differ in their impact on physical and cognitive fatigability, functional outcomes, symptom burden, and real-world treatment adherence. Because this is an observational study, no experimental treatments are given, and all clinical decisions remain the responsibility of the treating physicians. By examining fatigability in everyday clinical settings, this study aims to generate evidence that can help patients, families, and health care providers make more informed treatment decisions.

Подробное описание

This investigator-initiated, multicenter, prospective observational cohort study examines longitudinal changes in physical and cognitive fatigability among adults with multiple sclerosis (MS) initiating teriflunomide or dimethyl fumarate as part of routine clinical care. The study integrates standardized fatigability assessments into real-world clinical workflows across participating neurology centers.

Fatigability represents an objective performance decline during sustained motor or cognitive activity and provides information that is complementary to subjective fatigue ratings. To quantify physical fatigability, the study applies a structured 6-Minute Walk Test protocol in which distance covered during each minute is recorded. The primary physical fatigability index (DWI6-1) is calculated as the percentage change between the first and sixth minutes, enabling sensitive detection of time-dependent gait deterioration. Cognitive fatigability is quantified via a timed Symbol Digit Modalities Test procedure in which correct responses are recorded at three consecutive 30-second intervals. The Cognitive Fatigability Index (CFI-SDMT) reflects the proportional change between early and late test performance. Both indices allow continuous modeling of longitudinal trajectories and group differences.

All assessments are performed at baseline (within 30 days of treatment initiation) and at months 3, 6, 9, and 12. Functional performance measures (6MWT total distance, Timed 25-Foot Walk, Nine-Hole Peg Test), clinical evaluations (EDSS), patient-reported outcomes (FIS, TSQM, HADS), and MRI findings obtained during routine care are incorporated to contextualize patterns of fatigability. Test administration is standardized across centers through written manuals and joint training sessions. To minimize diurnal variability, fatigability tests are scheduled at approximately the same time of day for each participant.

Because the study is non-interventional, treatment decisions-including drug choice, dosing, and management of side effects-are determined solely by treating physicians. Data are recorded in a secure electronic capture platform using coded identifiers, with center-level access restrictions and prospective time-locked entry to maintain data integrity. All analyses follow a predefined statistical plan using mixed-effects modeling with participant- and center-level random effects to account for repeated measures and between-center heterogeneity.

This study aims to clarify real-world differences in fatigability trajectories between teriflunomide and dimethyl fumarate and to determine how these trajectories relate to functional performance, symptomatic burden, radiological disease activity, and treatment adherence in routine MS care.

Первичные конечные точки

• Walking Fatigability Index [Срок оценки: Assessments will be conducted at baseline, at three months, at six months, and at twelve months following treatment initiation.]
• Cognitive Fatigability Index [Срок оценки: Baseline, 3 months, 6 months, and 12 months]

Вторичные конечные точки (8)

• Walking Performance [Срок оценки: Baseline, 3 months, 6 months, and 12 months]
• Radiological Outcomes [Срок оценки: Radiological outcomes will be assessed at three time points: baseline (prior to treatment initiation), 6 months after starting treatment, and 12 months after starting treatment.]
• Walking Endurance [Срок оценки: Baseline, 3 months, 6 months, and 12 months]
• Processing Speed and Attention [Срок оценки: Baseline, 3 months, 6 months, and 12 months]
• Hand Coordination and Dexterity [Срок оценки: Baseline, 3 months, 6 months, and 12 months]
• Fatigue Severity [Срок оценки: Baseline, 3 months, 6 months, and 12 months]
• Treatment Satisfaction [Срок оценки: Baseline, 3 months, 6 months, and 12 months]
• Anxiety and Depression [Срок оценки: Baseline, 3 months, 6 months, and 12 months]

Критерии участия

Критерии включения

• Relapsing Multiple Sclerosis (RRMS or active SPMS) diagnosis, confirmed according to the 2017 revised McDonald criteria.
• 18 years or older at the time of enrollment.
• Newly initiated teriflunomide treatment as part of routine clinical care.
• Ambulatory status (EDSS ≤ 7.0), capable of completing study assessments.
• Ability and willingness to provide informed consent and comply with study procedures.

Критерии исключения

• Diagnosis of Primary Progressive Multiple Sclerosis (PPMS).
• Severe comorbidities affecting mobility or cognitive function (e.g., advanced cardiovascular, pulmonary, or neuromuscular disease).
• Neurological or psychiatric conditions that prevent cognitive testing (e.g., advanced cognitive impairment, untreated severe depression).
• Severe upper extremity motor dysfunction, limiting 9-Hole Peg Test (9-HPT) or Symbol Digit Modalities Test (SDMT) completion.
• Pregnancy or breastfeeding at the time of enrollment.
• Inability to comply with study visits at baseline, 3 months, 6 months, and 12 months.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Turkey (Türkiye) · 1 центр

• Erciyes University — Kayseri

Публикации

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• Bencsik K, Dobos E, Jobbagy Z, Birkas AJ, Kovacs K, Satori M, Lencses G, Bartok G, Losonczi E, Vecsei L, On Behalf Of The Teri-Real Investigators. Real-World Evidence for Favourable Quality-of-Life Outcomes in Hungarian Patients with Relapsing-Remitting Multiple Sclerosis Treated for Two Years with Oral Teriflunomide: Results of the Teri-REAL Study. Pharmaceuticals (Basel). 2022 May 13;15(5):598. PMID 35631424
• Elkhooly M, Bao F, Bernitsas E. Impact of Disease Modifying Therapy on MS-Related Fatigue: A Narrative Review. Brain Sci. 2023 Dec 20;14(1):4. doi: 10.3390/brainsci14010004. PMID 38275509
• Meca-Lallana JE, Prieto Gonzalez JM, Caminero Rodriguez AB, Olascoaga Urtaza J, Alonso AM, Duran Ferreras E, Espinosa R, Dotor J, Romera M, Ares Luque A, Perez Ruiz D, Calles C, Hernandez MA, Hervas Garcia M, Mendoza Rodriguez A, Berdei Montero Y, Tellez N, Herrera Varo N, Sotoca J, Presas-Rodriguez S, Querol Gutierrez LA, Hervas Pujol M, Batlle Nadal J, Martin Ozaeta G, Gubieras Lillo L, Martinez PMID 37861931
• Strosova D, Tuzil J, Turkova BV, Pilnackova BF, de Souza LL, Dolezalova H, Raskova M, Dufek M, Dolezal T. Relationship between Patient Preferences, Attitudes to Treatment, Adherence, and Quality of Life in New Users of Teriflunomide. Pharmaceuticals (Basel). 2022 Oct 11;15(10):1248. doi: 10.3390/ph15101248. PMID 36297360
• Miller AE. An updated review of teriflunomide's use in multiple sclerosis. Neurodegener Dis Manag. 2021 Oct;11(5):387-409. doi: 10.2217/nmt-2021-0014. Epub 2021 Sep 16. PMID 34486382
• Coyle PK, Khatri B, Edwards KR, Meca-Lallana JE, Cavalier S, Rufi P, Benamor M, Thangavelu K, Robinson M, Gold R; Teri-PRO Trial Group. Patient-reported outcomes in patients with relapsing forms of MS switching to teriflunomide from other disease-modifying therapies: Results from the global Phase 4 Teri-PRO study in routine clinical practice. Mult Scler Relat Disord. 2018 Nov;26:211-218. doi: 10.1 PMID 30273841

Идентификаторы

NCT: NCT06843382 · ROOF-MS

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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