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NCT Number: NCT06843382

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

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.

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Key information

Conditions

Multiple Sclerosis Autoimmune Diseases Autoimmune Diseases of the Nervous System Demyelinating Autoimmune Diseases, CNS Demyelinating Diseases Immune System Diseases Nervous System Diseases

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Erciyes University

Kayseri, Turkey (Türkiye)

Location contact

Mehmet Fatih Yetkin Assoc. Prof. MD, Assoc. Prof. MD

CONTACT

[email protected]

905428203060

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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.

Exclusion criteria

  • 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.

Treatment and study plan

Primary outcomes

  1. Walking Fatigability Index

    Time frame: Assessments will be conducted at baseline, at three months, at six months, and at twelve months following treatment initiation.

    Walking fatigability will be quantified using the Distance Walk Index (DWI), calculated with the following formula:

    DWI=(Distance at minute 6-Distance at minute 1Distance at minute 1)×100 DWI=(Distance at minute 1Distance at minute 6-Distance at minute 1 )×100

    A DWI decline of >10% will be classified as abnormal, based on prior relapsing-remitting MS studies.

    Unit of Measurement: Percentage (%) Time Frame: Baseline, 3 months, 6 months, and 12 months Higher Values Indicate: Better walking endurance (lower fatigability)

  2. Cognitive Fatigability Index

    Time frame: Baseline, 3 months, 6 months, and 12 months

    Cognitive fatigability will be quantified using the Cognitive Fatigability Index (CFI), calculated with the following formula:

    CFI=(SDMT3-SDMT1SDMT1)×100 CFI=(SDMT1SDMT3-SDMT1 )×100

    A negative CFI value will indicate cognitive fatigability, with a decline greater than 10% classified as abnormal.

    Unit of Measurement: Percentage (%) Higher Values Indicate: Better cognitive endurance (lower fatigability)

Secondary outcomes

  1. Walking Performance

    Time frame: Baseline, 3 months, 6 months, and 12 months

    Walking performance will be assessed using the 6-Minute Walk Test (6MWT). The total distance walked (meters) and walking speed (meters per minute, m/min) will be recorded.

    Unit of Measurement: Meters (m), Meters per minute (m/min) Higher Values Indicate: Better walking endurance

  2. Radiological Outcomes

    Time frame: 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.

    Radiological outcomes will assess MRI changes at baseline, 6 months, and 12 months to evaluate disease progression and lesion activity in MS.

    T2 Lesions: Total number of T2-weighted hyperintense lesions. Gadolinium-Enhancing Lesions: Presence and count of Gd-enhancing lesions. New Lesions: Number of newly developed brain and spinal cord lesions. Upper Cervical Spinal Lesions: Presence of lesions in C1-C4 spinal cord region. Brainstem Lesions: Identification of lesions in the brainstem.

    Unit: Lesion count per MRI scan Higher Values Indicate: Increased disease activity

  3. Walking Endurance

    Time frame: Baseline, 3 months, 6 months, and 12 months

    Walking endurance will be assessed using the 6-Minute Walk Test (6MWT). Participants will walk at their fastest pace to cover the maximum distance within six minutes, following the standardized protocol by Goldman et al. The total distance walked (meters) will be recorded as the primary measure of endurance.

    Unit of Measurement: Meters (m) Higher Values Indicate: Better walking endurance (lower fatigability)

  4. Processing Speed and Attention

    Time frame: Baseline, 3 months, 6 months, and 12 months

    Processing speed and sustained attention will be assessed using the Symbol Digit Modalities Test (SDMT), a validated neurocognitive test. Participants will complete the SDMT in a 90-second timed format following the standardized protocol.

    Correct responses will be recorded at three consecutive 30-second intervals, and the total number of correct responses will be reported.

    Unit of Measurement: Number of correct responses Higher Values Indicate: Better cognitive processing speed and sustained attention

  5. Hand Coordination and Dexterity

    Time frame: Baseline, 3 months, 6 months, and 12 months

    Hand coordination and dexterity will be evaluated using the 9-Hole Peg Test (9-HPT) for both hands. The time (in seconds) required to complete the task will be recorded.

    Unit of Measurement: Seconds (s) Higher Values Indicate: Worse dexterity

  6. Fatigue Severity

    Time frame: Baseline, 3 months, 6 months, and 12 months

    Fatigue severity will be evaluated using the Fatigue Impact Scale (FIS), a validated patient-reported measure assessing the perceived impact of fatigue on cognitive, physical, and psychosocial functioning. Participants rate the extent to which fatigue has affected daily activities during the previous month. Higher scores indicate greater fatigue-related impact.

    Time Frame: Baseline, Month 3, Month 6, Month 9, Month 12 Type of Outcome: Patient-Reported Outcome Measure Method of Aggregation: Mean change from baseline and longitudinal trajectory over 12 months.

  7. Treatment Satisfaction

    Time frame: Baseline, 3 months, 6 months, and 12 months

    Treatment satisfaction will be measured using the Treatment Satisfaction Questionnaire for Medication (TSQM). This instrument assesses satisfaction with medication across different domains (effectiveness, side effects, convenience, and global satisfaction).

    Unit of Measurement: TSQM Score (range to be specified) Higher Values Indicate: Greater treatment satisfaction

  8. Anxiety and Depression

    Time frame: Baseline, 3 months, 6 months, and 12 months

    Anxiety and depression symptoms will be assessed using the Hospital Anxiety and Depression Scale (HADS), which consists of two subscales:

    HADS-Anxiety (HADS-A): Scores range from 0 to 21, with higher scores indicating greater anxiety.

    HADS-Depression (HADS-D): Scores range from 0 to 21, with higher scores indicating greater depressive symptoms.

    Unit of Measurement: HADS Score (0-21 per subscale) Higher Values Indicate: Greater anxiety or depression

Other outcomes

  1. Safety outcomes

    Time frame: From enrollment through study completion at 12 months, with assessments at baseline, 3 months, 6 months, and 12 months

    The safety profile of teriflunomide will be assessed by monitoring the incidence, severity, and type of adverse events (AEs), including laboratory abnormalities, hair thinning or loss, and other treatment-related side effects. Serious adverse events (SAEs) will be categorized according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0), assessing their severity and relationship to treatment.

    Unit: Incidence count of AEs/SAEs

    Higher Values Indicate: Increased treatment-related adverse events

Study contacts

Contact information is provided by the study sponsor or research team.

Mehmet Fatih Yetkin Assoc. Prof. MD, Assoc. Prof.

CONTACT

[email protected]

905428203060

Sponsors and collaborators

Lead sponsor

TC Erciyes University

Other

Collaborators

  • Bursa Yuksek Ihtisas Training and Research Hospital
  • Kocaeli University
  • Sakarya University

Registry information

Official study title

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

Acronym: ROOF-MS

Important dates

Study start
2025
Primary completion
2027
Study completion
2027
First posted
Feb 25, 2025
Registry last updated
Nov 21, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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