PDF: Dalfampridine
(2016)Objective
Dalfampridine - To assess the effects of dalfampridine extended release (D-ER) 10 mg twice daily on accelerometer-based measures of ambulatory activity in people with multiple sclerosis, including intensity of walking and total amount of walking during daily activities
Study Summary
• Daily step count showed no significant difference: 148.7 vs 128.0 steps change (NS)
• Timed Up and Go test favored D-ER (p=0.042), but 6-Minute Walk Test showed no difference
Intervention
Dalfampridine extended release (D-ER) 10 mg twice daily orally for 4 weeks
Inclusion Criteria
Confirmed MS diagnosis by McDonald criteria, age 18-75 years, screening 6-Minute Walk Test distance 50-500 m, EDSS 0-6.5, MS-related walking difficulty
Study Design
Arms: Randomized crossover design with two sequences: D-ER/placebo (n=22) and placebo/D-ER (n=21), each period 4 weeks with 2-week washout between
Patients per Arm: 22 in sequence A (D-ER first), 21 in sequence B (placebo first); total 43 randomized
Outcome
• Secondary: TUG test favored D-ER (p=0.042); PADS-R total score favored D-ER (p=0.021)
• No differences in 6MWT, steps per day, or other accelerometer measures; well tolerated with no serious adverse events
Bottom Line
Dalfampridine extended release did not show a significant effect on accelerometer-measured ambulatory activity (primary endpoint: peak activity index) or daily step count in people with MS-related walking difficulty, though it showed benefit on the Timed Up and Go test and patient-reported physical activity measures; the study was well-tolerated with no serious adverse events
Major Points
- This was the first randomized controlled trial to evaluate dalfampridine effects on accelerometer-based measures of community ambulatory activity in MS
- Primary outcome (peak activity index - most intense 30 minutes of day) showed no significant difference: 0.6 strides/min increase with D-ER vs 0.3 with placebo (NS)
- Daily step count showed no significant difference: 148.7 steps increase with D-ER vs 128.0 with placebo (NS)
- All accelerometer-based measures (peak 5, 20, 60 minutes, percentage of day inactive) showed no significant differences
- Timed Up and Go test showed significant benefit favoring D-ER (p=0.042), suggesting D-ER may be more effective on brief clinic-based speed tests than continuous community monitoring
- 6-Minute Walk Test showed no significant difference between treatments
- Patient-reported PADS-R Total score significantly favored D-ER (p=0.021), suggesting perceived improvement in physical activity not captured by accelerometry
- MSWS-12 showed no significant differences, indicating no subjective walking improvement detected
- Responder analysis (≥20% increase in PAI) showed no treatment effect: 5 responders to D-ER, 5 to placebo, 2 to both
- Study completion rate was high: 41/43 (95.3%) completed the full crossover trial
- Treatment was well-tolerated with similar adverse event rates between D-ER and placebo; no serious adverse events occurred
Study Design
- Study Type
- Phase IV, single-center, randomized, double-blind, placebo-controlled, crossover trial
- Randomization
- Yes
- Blinding
- Double-blind; separate blinded evaluator performed all functional outcome measurements; active and placebo drugs appeared identical
- Sample Size
- 43
- Follow-up
- 10 weeks total (4-week period 1, 2-week washout, 4-week period 2, with 2-week telephone follow-up)
- Centers
- 1
- Countries
- United States
Primary Outcome
Definition: Change from baseline in peak activity index (PAI), defined as the average rate (strides per minute) of the most intensive 30 individual minutes during the day, measured by ankle-worn accelerometer (StepWatch3) during 7 days at baseline and week 3 of each treatment period
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | Placebo: Least squares mean change 0.3 ± 0.55 strides/min | - (Treatment effect 0.4 (95% CI 0.68)) | NS (p=0.586) |
Limitations & Criticisms
- Small sample size (43 participants randomized) may have limited statistical power to detect differences
- Single-center study limits generalizability of findings
- Crossover design may have introduced period and sequence effects, though statistical tests for these were negative
- Two-week washout period between treatment periods may have been too short to completely eliminate carryover effects from first period
- Accelerometer measurements were recorded during week 3 of each treatment period, which may not have been optimal therapeutic response time (described as 2-6 weeks in literature)
- Imbalance in sex distribution between groups (86% female in sequence A vs 52% in sequence B, p=0.022) though crossover design should mitigate this
- Study focused on routine daily activities over 7 days, which may have reduced detection of changes in peak walking performance
- Protocol did not require participants to attempt increases in physical activity, which might have revealed therapeutic effects
- Lack of Timed 25-Foot Walk test (primary outcome in pivotal D-ER trials) prevents direct comparison with responder definition from registration studies
- Study was not powered for secondary outcomes (TUG, 6MWT), limiting interpretation of these findings
- Absence of change in MSWS-12 suggests fundamental differences between this single-center population and larger multi-center studies showing D-ER responsiveness
- Accelerometers may not capture all relevant aspects of walking improvement, such as perceived ability to be more active or quality of gait
- Brief clinic-based tests (TUG, T25FW) may be more sensitive to D-ER effects than passive community recordings
- No minimal clinically important difference established for primary outcome (PAI), making clinical significance of findings uncertain
- Study excluded patients with conditions preventing 6MWT, potentially limiting applicability to more severely disabled MS population
Citation
Brown TR, Simnad VI. A Randomized Crossover Trial of Dalfampridine Extended Release for Effect on Ambulatory Activity in People with Multiple Sclerosis. Int J MS Care. 2016;18:170-176