PHILADELPHIA, Pennsylvania — Results of a new analysis show that patients with relapsing-remitting multiple sclerosis (RRMS) who had confirmed improvement in walking speed (CIWS) had better self-reported physical functioning, and treatment with natalizumab (Tysabri, Biogen Idec) improved the probability of achieving a CIWS.
"The majority of patients with an improvement in the walking speed did not show an improvement in the EDSS [Expanded Disability Status Scale]...suggesting that the walking speed is more sensitive to walking than is EDSS," Richard Rudick, MD, vice chairman for research and development in the Neurological Institute at the Cleveland Clinic Foundation, Ohio, concluded.
He said 75% of patients receiving natalizumab who had improved walking speed did not show improvement on the EDSS.
This new analysis of data from the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial was presented here at the American Academy of Neurology (AAN) 66th Annual Meeting.
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Previous studies have shown that the timed 25-foot walk test may be more sensitive to improvements in ambulation ability compared with the EDSS.
The walking speed is more sensitive to walking than is EDSS. Dr. Richard Rudick
The AFFIRM trial tested the safety and efficacy of natalizumab as monotherapy (n = 627) compared with placebo (n = 315) in RRMS. The main results of AFFIRM, published in 2006 in the New England Journal of Medicine, showed natalizumab reduced disability progression and clinical relapses vs placebo.
The 2 groups of the study were well matched for age (35.6 to 36.7 years), sex (about two thirds female), disease duration (median, 5.0 to 6.0 years), number of relapses in the past year (mean, 1.5), EDSS score (mean, 2.3), distance on timed 25-foot walk test (mean, 5.4 seconds), and Short Form-36 physical component score (mean, about 44).
In a previous survey of patients regarding 13 bodily functions, walking topped the ranking as the most important one for most patients, whether they had had MS up to 5 years (38%; n = 82) or 15 years or more (28%; n = 80). Next most important was visual function, beating out hand function, pain, bladder or bowel control, thinking and memory, speech, and swallowing.
The objective of this post hoc analysis of the AFFIRM study was to determine the effect of natalizumab on the proportion of patients with CIWS at 3 months, and importantly, to determine the clinical relevance of this measurement to patient-reported physical health.
Meaningful Improvements
A greater proportion of patients receiving natalizumab had CIWS over 2 years compared with placebo recipients, Dr. Rudick reported.
In addition, the drug improved the probability of CIWS, and CIWS was associated with a significantly positive change in patient-reported physical health.
Table. Improvement in CIWS
| Time Point | Patients with ≥15% CIWS: Natalizumab (%) | Patients with ≥15% CIWS: Placebo (%) | P Valuea | Patients with ≥20% CIWS: Natalizumab (%) | Patients with ≥20% CIWS: Placebo (%) | P Valuea |
| Year 0 - 1 | 11 | 7 | .03 | 7 | 4 | .09 |
| Year 0 - 2 | 19 | 12 | .011 | 12 | 7 | .013 |
| a P value vs placebo. | ||||||
Most of the improvement in walking speed occurred during the first year for both the natalizumab and placebo groups and was maintained or increased by year 2.
At 1 year, patients receiving natalizumab had a 76% relative increase in CIWS of at least 20% compared with the placebo group (P = .09), and at 2 years the relative increase in CIWS was 78% (P = .01).
CIWS was also associated with better physical functioning. "Those with confirmed improvement in walking speed at 20% had a mean of 2.7 improvement on the PCS [SF-36 physical component score] while those without confirmed improvement essentially did not change [P = .002]," Dr. Rudick reported.
The effects on CIWS were larger and occurred earlier in patients with higher baseline disability as gauged by the EDSS score. However, patients with CIWS did not have a 3-month confirmed 1.0-point or greater improvement in EDSS score, "indicating that the confirmed improvement in walking speed is a much more direct measure of walking than is EDSS," Dr. Rudick said. So CIWS may be more sensitive than EDSS as an indicator of improved ambulation in patients with RRMS.
Components of Disability
Bruce Cree, MD, PhD, MCR, associate professor of clinical neurology at the University of California, San Francisco, commented to Medscape Medical News that "neither the EDSS nor the timed 25-foot walk...nor the Symbol Digit Modalities Test captures all of what patients experience. And so, we measure only components of disability. There is a lot more that goes beyond the standard metrics that are used in clinical trials, and those are just as important to the patients and address things such as vocation and other aspects that are not captured by neurological exam."
Dr. Cree noted that no clinical trial in MS has yet used a patient-reported outcome as the primary endpoint, but some have used such an outcome as a secondary or tertiary endpoint.
"I think it's very provocative if you had a remarkable result on a general disability assessment for patients where the patients really felt that they were doing a whole lot better and you saw some discrepancy or discordance from, say for example, the timed 25-foot walk, the question is which is really more relevant, something that you measure with a stop watch or what the patient tells you?" He said such a question needs to be addressed for future studies.
But Robert Naismith, MD, assistant professor of neurology at Washington University in St. Louis, Missouri, said the 25-foot timed walk can still be useful in explaining to patients what they may expect with some of the treatments.
"It may be difficult to convey it in terms [that] your EDSS score may or may not improve by this proportion, but to put it in terms of walking, I think that really resonates with them," he told Medscape Medical News.
He also pointed out that walking speed on the test correlates with patient walking ability in daily life, so the test is a useful parameter. Furthermore, payers are increasingly interested in exactly how medications help patients, and they want to select ones that have the best evidence that they provide a benefit. Dr. Naismith predicted that clinical tests that can translate into practical benefits for patients will be used more often in clinical trials.
MOBILE: Fampridine Walking Results
The authors of another study called MOBILE, led by Jan Lycke, MD, from the Institute of Neuroscience and Physiology at the Sahlgrenska Academy in Gothenburg, Sweden, also presented here during the emerging science session at the meeting, noted that walking is a multidimensional function and is controlled by complex domains.
MOBILE, a randomized, double-blind study, compared the effects at 24 weeks of prolonged-release fampridine, 10 mg twice daily, with those of placebo. Fampridine is approved as an agent to improve walking in patients with MS.
In addition to walking speed, the investigators evaluated patients with various forms of MS (primary progressive, secondary progressive, progressive-relapsing, or RRMS) for walking ability and dynamic and static balance using the 12-item Multiple Sclerosis Walking Scale (MSWS-12), the Timed Up and Go (TUG) test, and the Berg Balance Scale (BBS).
The timed TUG test measures mobility and dynamic balance by asking patients to stand from a seated position, walk out 3 meters, turn around, walk back to the chair, and sit down.
A higher proportion of patients receiving active drug vs placebo had clinically meaningful improvements on the MSWS-12 (P = .015) and on the TUG test (P = .026). They also had better BBS total scores.
The authors concluded that prolonged-release fampridine provided clinically meaningful and sustained improvement in walking ability and balance over the 24-week treatment period.
They said the study established clinically meaningful thresholds for the MSWS-12 and TUG speed and demonstrated the additional benefits of a broader range of objective and patient-reported measures of walking ability.
The AFFIRM study was supported by Biogen Idec. Dr. Rudick has received research support and honoraria or consulting fees from Biogen Idec, Novartis, and Genzyme Corporation and will begin employment with Biogen Idec on May 12, 2014. He has received license fee payments from a patent. Dr. Cree received personal compensation from AbbVie, Biogen Idec, EMD Serono, Genzyme/Sanofi Aventis, MedImmune, Novartis, and Teva Neurosciences and has conducted clinical trials with many of those organizations, as well as Hoffmann-La Roche. Dr. Naismith has consulted for Acorda, Biogen Idec, Bayer, EMD Serono, Genzyme, Genentech, and Questcor.The MOBILE study was funded by Biogen Idec. Dr. Lycke has received personal compensation for activities with Biogen Idec, Bayer Schering, Genzyme, Merck Serono, Sanofi-Aventis, and Novartis and has received research support from Biogen Idec, Novartis, and TEVA.
American Academy of Neurology (AAN) 66th Annual Meeting. AFFIRM study: Abstract S4.006. Presented April 29, 2014. MOBILE study: Abstract 010 in the Emerging Science session. Presented April 30, 2014.
