A Randomized Crossover Trial of Dalfampridine Extended Release for Effect on Ambulatory Activity in People with Multiple Sclerosis.
ABSTRACT: Dalfampridine extended release (D-ER) is indicated to improve walking in people with multiple sclerosis (MS) as demonstrated by an increase in walking speed. This study assessed the effects of D-ER on accelerometer-based measures in people with MS, including intensity of walking and total amount of walking during daily activities.In this double-blind placebo-controlled crossover study, people with MS-related walking difficulty were randomized (1:1) to receive 4 weeks of D-ER 10 mg twice daily and 4 weeks of placebo in either order separated by a 2-week washout. Participants wore accelerometers for 7 days at baseline and week 3 of each on-drug period. The primary outcome was the peak activity index (PAI), defined as the most intense 30 individual minutes of the day (strides per minute). Secondary outcomes included daily step count, 6-Minute Walk Test (6MWT), Timed Up and Go (TUG) test, and patient-reported outcomes. A mixed-effects repeated-measures statistical model was used.Forty-three participants were randomized (mean Expanded Disability Status Scale score, 5.17). Least squares mean (standard error) change from baseline on the PAI was 0.6 (0.54) strides/min on D-ER and 0.3 (0.55) strides/min on placebo and in daily step count was 148.7 (222.4) on D-ER and 128.0 (225.4) on placebo. Other accelerometer-based measures and the 6MWT showed no significant differences between D-ER and placebo. The TUG test (P = .042) favored D-ER. There were no serious adverse events.Dalfampridine did not show an effect on accelerometer-measured ambulatory activity in people with MS-related walking difficulty. More work is needed to confirm these results.
Project description:Background:Ecological validity is an important psychometric property when assessing function. How a person with multiple sclerosis (MS) performs in clinical settings and in natural environments can be quite different. Walking is the most frequently assessed and recommended way to maintain health in a progressive disease such as MS. The objective was to estimate the extent to which clinical tests of walking capacity differ from real-world walking performance in people with MS. Methods:Ninety-eight women and 27 men with MS were assessed using the 6-Minute Walk Test (6MWT) and wore an accelerometer for 7 consecutive days. Mean number of steps, mean number of steps at a brisk cadence or faster, and cumulative time per week spent walking at a brisk cadence or faster were regressed on 6MWT categories using quantile (median) regression. Contiguous steps were grouped into bouts of less than 5 minutes and 5 minutes or longer, and number of bouts 5 minutes or longer was regressed on 6MWT categories using a zero-inflated Poisson model. Results:A total of 869 patient-days of accelerometer data were available. Mean total number of steps per day was greater for people with higher walking capacity (6MWT distance, ?600 m). However, this group spent a small proportion of time walking at higher cadence bands. Compared with people with 6MWT distance of at least 600 m, people walking less than 500 m had approximately half the rate of walking bouts of 5 minutes or longer. Positive mood and fewer exercise barriers predicted more walking bouts of at least 5 minutes. Conclusions:Study participants with MS spent a small proportion of time walking at a health-promoting intensity.
Project description:The standard functional tool for gait assessment in multiple sclerosis (MS) clinical trials has been the 25-Foot Timed Walk Test, a measure of gait speed. Straight-line gait assessment may not reflect adequately upon balance and coordination. Walking tests with turns may add additional information towards understanding gait and balance status, and be more reflective of ambulation in the community. Understanding the impact of turn parameters on patient-reported outcomes of balance and walking would help MS clinicians better formulate treatment plans for persons with gait limitations. In this study, ninety-one persons with MS (Expanded Disability Status Score; EDSS, range: 0-6.5) were enrolled in an initial cross-sectional study. Twenty-four subjects (EDSS, range:1.0-6.0) completed a follow-up visit an average of 12 months later. Spatiotemporal gait analysis was collected at both visits using APDM Opal wireless body-worn sensors while performing the Timed-Up-and-Go (TUG) and 6-Minute Walk Test (6MWT). For both cross-sectional and longitudinal data, regression analyses determined the impact on the addition of turning parameters to stride velocity (SV), in the prediction of self-reported balance confidence (Activities-Specific Balance Confidence Scale (ABC)) and walking limitation (12-item Multiple Sclerosis Walking Scale (MSWS-12)). The addition of 6MWT peak turn velocity (PTV) to 6MWT SV increased the predictive power of the 6MWT for the ABC from 20% to 33%, and increased the predictive power from 28% to 41% for the MSWS-12. TUG PTV added to TUG SV also strengthened the relationship of the TUG for the ABC from 19% to 28%, and 27% to 36% for the MSWS-12. For those with 1 year follow-up, percent change in turn number of steps (TNS%?) during the 6MWT added to 6MWT SV%? improved the modeling of ABC%? from 24% to 33%. 6MWT PTV%? added to 6MWT SV%? increased the predictive power of MSWS-12%? from 8% to 27%. Conclusively, turn parameters improved modeling of self-perceived balance confidence and walking limitations when added to the commonly utilized measure of gait speed. Tests of longer durations with multiple turns, as opposed to shorter durations with a single turn, modeled longitudinal change more accurately. Turn speed and stability should be qualitatively assessed during the clinic visit, and use of multi-faceted tests such as the TUG or 6MWT may be required to fully understand gait deterioration in persons with MS.
Project description:OBJECTIVE:To investigate feasibility of multiple sclerosis (MS) exercise guidelines for inactive people with MS (PwMS) and to examine preliminary efficacy for walking. To investigate effect of augmenting that intervention with education based on social cognitive theory (SCT). DESIGN:Pilot multicentre, double-blind, randomised, parallel, controlled trial. SETTING:Community-delivered programme. PARTICIPANTS:Sixty-five physically inactive PwMS walked independently, scored 0-3 on the Patient Determined Disease Steps Scale, had no MS relapse or change in MS medication in 12?weeks. INTERVENTIONS:10-week exercise plus SCT education (SCT) compared with exercise plus attention control education (CON). OUTCOME MEASURES:Six-Minute Walk Test (6MWT), Timed Up and Go (TUG) test and Multiple Sclerosis Walking Scale-12 (MSWS-12). RESULTS:174 expressed interest, 92 were eligible and 65 enrolled (SCT, n=32; CON, n=33). The intervention was feasible and delivered as intended. 68% of SCT group and 50% of control group met the exercise guidelines after intervention. Using linear mixed effects models, intention-to-treat basis, there was insufficient evidence for difference between the groups over the trial (6MWT, p=0.30; TUG, p=0.4; MSWS-12, p=0.8). Using secondary analysis of a cohort with data for?3?assessments (SCT, n=21; CON, n=20), there was significant treatment effect favouring the intervention group (p=0.04) with mean effect for 6MWT 39.0?m (95%?CI 2.26 to 75.73) at 12?weeks and 40.0?m (95%?CI 2.3 to 77.8) at 36?weeks. Both groups improved significantly in 6MWT following 10-week intervention (SCT, mean ?=83.02, SD=60.1, p?0.01; CON, mean ?=56.92, SD=73.5, p?0.01), TUG (SCT, ?=-0.70, SD=1.25, p?0.01; CON, ?=-0.54, SD=0.95, p?0.01) and MSWS-12 (SCT, ?=-8.03, SD=16.18, p=0.02; CON, ?=-0.86, SD=18.74, p=0.81). CONCLUSIONS:A 10-week exercise programme based on the MS exercise guidelines for improving walking in previously inactive PwMS was feasible. There is marginal evidence of a treatment effect in favour of the exercise plus SCT intervention at 12 and 36 weeks. TRIAL REGISTRATION NUMBER:NCT02301442; Results.
Project description:Mobility impairment is a common disability in MS and negatively impacts patients' lives.Evaluate the effect of prolonged-release (PR) fampridine (extended-release dalfampridine in the United States) on self-assessed walking disability, dynamic/static balance and safety in patients with MS.MOBILE was a randomised, double-blind, exploratory, placebo-controlled trial. Patients with progressive/relapsing-remitting MS and Expanded Disability Status Scale score of 4.0-7.0 were treated with PR-fampridine or placebo twice daily for 24 weeks. Efficacy endpoints included change from baseline in the 12-item MS Walking Scale (MSWS-12), Timed Up and Go (TUG) test and Berg Balance Scale (BBS).132 patients were randomised at 24 sites in six countries. PR-fampridine therapy resulted in greater median improvements from baseline in MSWS-12 score, TUG speed and BBS total score versus placebo over 24 weeks. A higher proportion of patients receiving PR-fampridine versus placebo experienced significant improvements at MSWS-12 improvement thresholds ?7 (p = 0.0275), ?8 (p = 0.0153) and ?9 points (p = 0.0088) and TUG speed thresholds ?10% (p = 0.0021) and ?15% (p = 0.0262). PR-fampridine was well tolerated.PR-fampridine therapy resulted in early and sustained improvements in broad measures of walking and balance over six months.
Project description:OBJECTIVES:To identify exercise tests that are suitable for home-based or remote administration in people with chronic lung disease. METHODS:Rapid review of studies that reported home-based or remote administration of an exercise test in people with chronic lung disease, and studies reporting their clinimetric (measurement) properties. RESULTS:84 studies were included. Tests used at home were the 6-minute walk test (6MWT, two studies), sit-to-stand tests (STS, five studies), Timed Up and Go (TUG, 4 studies) and step tests (two studies). Exercise tests administered remotely were the 6MWT (two studies) and step test (one study). Compared to centre-based testing the 6MWT distance was similar when performed outdoors but shorter when performed at home (two studies). The STS, TUG and step tests were feasible, reliable (intra-class correlation coefficients >0.80), valid (concurrent and known groups validity) and moderately responsive to pulmonary rehabilitation (medium effect sizes). These tests elicited less desaturation than the 6MWT, and validated methods to prescribe exercise were not reported. DISCUSSION:The STS, step and TUG tests can be performed at home, but do not accurately document desaturation with walking or allow exercise prescription. Patients at risk of desaturation should be prioritised for centre-based exercise testing when this is available.
Project description:BACKGROUND:Walking impairment is a hallmark of multiple sclerosis (MS). It affects?>?90% of individuals over time, reducing independence and negatively impacting health-related quality of life, productivity, and daily activities. Walking impairment is consistently reported as one of the most distressing impairments by individuals with MS. Prolonged-release (PR)-fampridine previously has been shown to improve objectively measured walking speed in walking-impaired adults with MS. The impact of PR-fampridine from the perspective of the individual with MS warrants full and detailed examination. OBJECTIVE:The objective of this study was to evaluate whether PR-fampridine has a clinically meaningful effect on self-reported walking ability in walking-impaired participants with MS. METHODS:ENHANCE was a phase III, randomized, double-blind, placebo-controlled study of PR-fampridine 10 mg twice daily in walking-impaired individuals age 18-70 years with either relapsing or progressive forms of MS and an Expanded Disability Status Scale (EDSS) score of 4.0-7.0 at screening. Participants were stratified by EDSS score (??6.0 or 6.5-7.0) at randomization to ensure a balanced level of disability in the treatment groups. The primary endpoint was the proportion of participants with a mean improvement in the 12-item Multiple Sclerosis Walking Scale (MSWS-12) score exceeding the predefined threshold for clinically meaningful improvement (??8 points) over 24 weeks. Secondary endpoints included the proportion with???15% improvement in Timed Up and Go (TUG) speed, and mean changes in Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS), Berg Balance Scale (BBS), and ABILHAND scores over 24 weeks. RESULTS:In total, 636 participants with MS were randomized (PR-fampridine, n?=?317; placebo, n?=?319; modified intention-to-treat sample: PR-fampridine, n?=?315; placebo, n?=?318). At baseline in the PR-fampridine and placebo groups, 46% and 51% had a progressive form of MS, median [range] EDSS scores were 6.0 [4.0-7.0] and 5.5 [4.0-7.0], mean [range] MSWS-12 scores were 63.6 [0-100] and 65.4 [0-100], and mean [range] TUG speed was 0.38 [0.0-1.0] and 0.38 [0.0-1.2] feet/s, respectively. A significantly higher percentage of PR-fampridine-treated participants (136/315 [43.2%]) had clinically meaningful improvement in MSWS-12 score over 24 weeks versus placebo (107/318 [33.6%]; odds ratio 1.61 [95% confidence interval 1.15-2.26]; p?=?0.006). For PR-fampridine versus placebo, significantly more participants had a???15% improvement in TUG speed, and there was significantly greater mean improvement in MSIS-29 PHYS score (p?<?0.05); numerical improvements that were not statistically significant were observed in BBS/ABILHAND. Adverse events that were more common in the PR-fampridine group than placebo group (difference???3%) by Medical Dictionary for Regulatory Activities (MedDRA®) Preferred Term were urinary tract infection and insomnia. There were no seizures reported. CONCLUSIONS:PR-fampridine treatment resulted in sustained, clinically meaningful improvements over 24 weeks in self-reported walking and functional ability in walking-disabled participants with MS. CLINICALTRIALS. GOV IDENTIFIER:NCT02219932.
Project description:<h4>Background</h4>To date, detailed analyses of walking patterns using accelerometers during the 6-min walk test (6MWT) have not been performed in patients with chronic obstructive pulmonary disease (COPD). Therefore, it remains unclear whether and to what extent COPD patients have an altered walking pattern during the 6MWT compared to healthy elderly subjects.<h4>Methodology/principal findings</h4>79 COPD patients and 24 healthy elderly subjects performed the 6MWT wearing an accelerometer attached to the trunk. The accelerometer features (walking intensity, cadence, and walking variability) and subject characteristics were assessed and compared between groups. Moreover, associations were sought with 6-min walk distance (6MWD) using multiple ordinary least squares (OLS) regression models. COPD patients walked with a significantly lower walking intensity, lower cadence and increased walking variability compared to healthy subjects. Walking intensity and height were the only two significant determinants of 6MWD in healthy subjects, explaining 85% of the variance in 6MWD. In COPD patients also age, cadence, walking variability measures and their interactions were included were significant determinants of 6MWD (total variance in 6MWD explained: 88%).<h4>Conclusions/significance</h4>COPD patients have an altered walking pattern during 6MWT compared to healthy subjects. These differences in walking pattern partially explain the lower 6MWD in patients with COPD.
Project description:In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS).Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT).Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW.We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders.The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.
Project description:BACKGROUND:Walking capacity tests are commonly used to evaluate interventions aiming at reducing walking impairment in people with multiple sclerosis (pwMS). However, their ecological validity has recently been questioned. The aim of the present study was to investigate the ecological validity of the 2- and 6-minutes walking tests (2MWT and 6MWT) and the timed 25-foot walk (T25FW) after 28 days of multidisciplinary inpatient rehabilitation (MIR) in pwMS using accelerometry. METHODS:PwMS wore an accelerometer on 7 consecutive days within a 14-day period prior to MIR, performed 2/6MWT and T25FW at the beginning and at the end of MIR, followed by another 7 consecutive days of accelerometry. RESULTS:Significant improvements in 2/6MWT and T25FW after MIR in a cohort of 76 pwMS (mean age = 47.9, SD 8.3 years) were overall correlated to a significant gain in everyday life mobility (total steps/day). However, the correlation was strongly dependent on pre-existing walking disability defined by EDSS and only pwMS with "mild" walking impairment (EDSS 2-3.5) were able to transfer benefits measurable by walking capacity tests into improved everyday life mobility, while pwMS with "moderate to severe" walking disability (EDSS 4-6.5) were not. CONCLUSION:Ecological validity of changes in walking capacity tests following MIR is strongly dependent on pre-existing walking impairment.
Project description:Engaging in physical activity (PA) is a key aspect in the management of axial spondyloarthritis (axial SpA), however, its relationship with clinical measures is unknown. Previous research has mainly focused on subjective methods of measuring PA and sedentary behaviour (SB). The aim of this study was to explore the associations between objectively measured PA and SB with clinical measures in people with established axial SpA. Fifty participants were recruited from secondary-care rheumatology outpatient services in Glasgow, UK. Clinical measures collected included; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Ankylosing Spondylitis Quality of Life (ASQOL) and the Six Minute Walk Test (6MWT). PA and SB were measured using the activPAL3 tri-axial accelerometer. Data from forty-five participants were included (23 males, average age 49?±?12 years). Participants accumulated an average of 93.2?±?41.5 min/day walking with an average of 7200?±?3397 steps/day. The majority of the day (65%) was spent sitting, accumulated in prolonged bouts. Walking time and steps taken/day were associated with better BASFI (r?=?- 0.395, p?=?0.007 and r?=?- 0.404, p?=?0.006), ASQOL (r?=?- 0.375, p?=?0.011 and r?=?- 0.361, p?=?0.015) and 6MWT (r?=?0.396, p?=?0.007 and r?=?0.421, p?=?0.004); while longer walking events were associated with better BASMI (rho?=?- 0.352, p?=?0.018), BASFI (rho?=?- 0.316, p?=?0.034) and 6MWT (rho?=?0.404, p?=?0.006). SB was associated with worse ASQOL (r?=?0.380, p?=?0.010) and 6MWT (6MWT, r?=?- 0.357, p?=?0.016). In people with axial SpA PA is associated with better function, exercise capacity and spinal mobility, while SB is associated with lower exercise capacity and poor quality of life. These findings support the promotion of PA and reduction of SB in people with axial SpA.