Measuring Disability Progression with the Multiple Sclerosis Functional Composite at eight-year follow-up.29 MSFC baseline scores were strongly
correlated with MSFC scores at two and eight years, whereas there was a more moderate correlation between baseline EDSS scores and EDSS scores at two and eight years. Additionally, baseline MSFC scores and change in the MSFC over two years were correlated with both EDSS scores and brain atrophy (measured by brain parenchymal fraction with MRI) at the eight-year follow-up.29
Despite this
demonstrated high predictive validity in RRMS, a study of 161 patients with primary progressive MS found that short-term worsening in both the MSFC and EDSS had poor predictive validity of future disability.30
Clinical Trials Using the Multiple Sclerosis Functional Composite
The MSFC has been used in several clinical trials, primarily as a supplement to the EDSS rather than a replacement measure of disability. The MSFC was not available in early phase III trials of first-line DMTs, but has been used in further clinical trials of IFNβ-1a, IFNβ-1b and glatiramer acetate. Newer phase III trials have incorporated the MSFC as a secondary outcome measure, including trials of natalizumab, fingolimod and teriflunomide. The MSFC was not reported in the phase III study of cladribine.12
Inteferon Beta-1a
The MSFC was first used as a primary outcome measure in a phase III placebo-controlled study of IFNβ-1a in secondary progressive MS (IMPACT).31
The median MSFC z-score change was reduced by 40.4%
in IFNβ-1a patients compared with placebo, whereas there was no benefit demonstrated by the EDSS.31
These findings suggest that the
MSFC is more sensitive to change in disability than is the EDSS. Interferon Beta-1b
Patients with a clinically isolated syndrome, including a first neurologic event and two or more clinically silent MRI lesions, were given either subcutaneous IFNβ-1b (Betaseron®) or placebo every other day for two years or until they developed MS. They were then eligible to enter a follow-up study involving continuing IFNβ-1b or switching from placebo to IFNβ-1b for three additional years to assess whether early treatment had an effect on disability progression. Early treatment had a beneficial effect on six-month-confirmed EDSS disability progression three years after the initial neurologic event, suggesting that a treatment delay early in the course of disease affects later disability accumulation. However, the MSFC did not detect any relevant deterioration in either group and there was no difference between groups in their overall scores. The investigators were surprised by this finding because the MSFC was designed to improve sensitivity to change compared with the EDSS. However, the authors concluded that the MSFC might not be suitable in measuring disability early during the course of disease because domains not included in the MSFC (i.e. visual and sensory function) are often more affected in early MS than are those domains measured by the MSFC (i.e. arm dexterity, ambulation and cognition).33
The MSFC was used as a secondary outcome measure in the phase III trial of Betaseron in newly emerging MS for initial treatment (BENEFIT).32
The MSFC was also used as a secondary outcome measure in a randomised placebo-controlled pilot trial of IFNβ-1b in 73 patients with primary progressive or transitional MS. There was no difference between groups in disability progression as measured by the EDSS; however, there was a significant difference in MSFC scores favouring IFNβ-1b,34
suggesting better sensitivity of the MSFC in this study. EUROPEAN NEUROLOGICAL REVIEW Natalizumab
The MSFC was a secondary efficacy end-point identified in the placebo-controlled phase III trial of natalizumab (Tysabri®) monotherapy in relapsing MS (The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing–Remitting MS [AFFIRM]).7
Glatiramer Acetate
The MSFC was used as a secondary disability end-point in a large placebo-controlled trial of glatiramer acetate (Copaxone®) in primary progressive MS (PROMiSE).35
score were not significantly different in the placebo or treatment groups, and the study was terminated early.35
Changes in both the MSFC and EDSS
Natalizumab reduced
disability progression compared with the placebo as measured by both the EDSS and MSFC. There was a significant difference in MSFC z-score change from baseline apparent after 12 weeks of treatment, which was maintained over two years.36
The MSFC was also used as a
secondary efficacy end-point in the trial of natalizumab plus IFNβ-1b versus IFNβ-1b alone (The Safety and efficacy of antegren in combination with IFNβ-1a in subjects with relapsing-remitting MS [SENTINEL] trial).8
Similarly, the natalizumab-treated group had a reduced risk of disability progression as measured by the EDSS and MSFC compared with IFNβ-1b alone. There was a significant difference between groups in the MSFC z-score change from baseline that was apparent 48 weeks after beginning natalizumab and sustained over two years.36
Fingolimod
The MSFC was also a secondary efficacy end-point in the two recently published Phase III trials of fingolimod in RRMS. In the phase III placebo-controlled trial of oral Fingolimod for relapsing MS (FREEDOMS) study,10
both EDSS scores and MSFC z-scores remained
EDSS and MSFC z-score changes were similar and both measures were generally better in fingolimod-treated groups than in the IFNβ-1b group. Figure 1 displays a comparison between the 24-month z-score change in EDSS and in MSFC from baseline in the fingolimod and placebo groups in the FREEDOMS study.10 Figure 2 displays a similar comparison of 12-month z-score change in EDSS and in MSFC in the fingolimod and IFNβ-1b groups in the TRANSFORMS study.11
Changes in EDSS and MSFC z-scores in a
given treatment group were similar, which suggests that the MSFC did not provide a much more sensitive measure of disability in these trials.
Clinical Relevance of the Multiple Sclerosis Functional Composite
To interpret MSFC scores in both clinical trials and individual patients, it is important to understand meaningful changes in the MSFC. It has been suggested that a 20% change in the 25FTW and 9HPT represents a reliably true change in function, whereas lower levels of change might represent clinically insignificant day-to-day fluctuations.37
In
addition, it has been suggested that an increase of more than 20% in the 25FTW or 9HPT also indicates a clinically significant impact on disability, as perceived by patients with MS.38–40
relevant change in the overall MSFC score has not yet been determined.41
However, the clinically This limits the usefulness of the MSFC as an outcome 33
stable or improved slightly in the fingolimod groups, but worsened in the placebo group. Similarly, in the phase III study of oral fingolimod versus IFNβ-1b (Trial assessing injectable interferon versus FTY720 oral in relapsing–remitting multiple sclerosis [TRANSFORMS]),11
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