Real-world Experience of Oral Agents On Fatigability in Multiple Sclerosis (ROOF-MS)

November 18, 2025 updated by: Mehmet Fatih Yetkin, TC Erciyes University

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

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.

Study Type

Observational

Enrollment (Estimated)

100

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Mehmet Fatih Yetkin Assoc. Prof. MD, Assoc. Prof.
  • Phone Number: 905428203060
  • Email: drfatihmehmet@gmail.com

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

The study population will consist of adult patients aged 18 years or older with a confirmed diagnosis of relapsing Multiple Sclerosis (MS), including relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS), according to the 2017 revised McDonald criteria. Participants will be selected from routine clinical settings where teriflunomide has been prescribed as part of standard care. Eligible individuals must be ambulatory, with an Expanded Disability Status Scale (EDSS) score of 7.0 or lower, and capable of performing the 6-Minute Walk Test (6MWT). This population will represent a real-world cohort reflective of patients receiving teriflunomide in typical clinical practice.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Teriflunomide Cohort
Participants with relapsing multiple sclerosis who initiate teriflunomide as part of routine clinical care. Individuals in this cohort undergo standardized assessments of physical and cognitive fatigability, functional performance, clinical status, patient-reported outcomes, and routinely obtained MRI findings at baseline and at 3, 6, 9, and 12 months. No experimental treatment is administered, and all therapeutic decisions remain under the responsibility of the treating physician.
Dimethyl Fumarate Cohort
Participants with relapsing multiple sclerosis who initiate dimethyl fumarate as part of routine clinical care. Individuals in this cohort complete standardized evaluations of physical and cognitive fatigability, functional performance, clinical status, patient-reported outcomes, and routinely acquired MRI measures at baseline and at 3, 6, 9, and 12 months. No experimental intervention is provided, and all treatment decisions are made independently by the treating physician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
Assessments will be conducted at baseline, at three months, at six months, and at twelve months following treatment initiation.
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)
Baseline, 3 months, 6 months, and 12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Baseline, 3 months, 6 months, and 12 months
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
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
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)
Baseline, 3 months, 6 months, and 12 months
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
Baseline, 3 months, 6 months, and 12 months
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
Baseline, 3 months, 6 months, and 12 months
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
Baseline, 3 months, 6 months, and 12 months
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
Baseline, 3 months, 6 months, and 12 months
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.
Baseline, 3 months, 6 months, and 12 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
From enrollment through study completion at 12 months, with assessments at baseline, 3 months, 6 months, and 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

TC Erciyes University

Collaborators

Kocaeli University
Sakarya University
Bursa Yuksek Ihtisas Training and Research Hospital

Investigators

  • Principal Investigator: Mehmet Fatih Yetkin Assoc. Prof. MD, Assoc. Prof., TC Erciyes University
  • Study Chair: Husnu Efendi, Prof., Kocaeli University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

November 20, 2025

Primary Completion (Estimated)

June 15, 2027

Study Completion (Estimated)

June 15, 2027

Study Registration Dates

First Submitted

January 22, 2025

First Submitted That Met QC Criteria

February 21, 2025

First Posted (Actual)

February 25, 2025

Study Record Updates

Last Update Posted (Actual)

November 21, 2025

Last Update Submitted That Met QC Criteria

November 18, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ROOF-MS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

all IPD that underlie results in a publication

IPD Sharing Time Frame

Beginning 3 months and ending 3 years after the publication of results

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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