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Dalfampridine Longterm

Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials

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Year of Publication: 2015

Authors: Andrew D Goodman, Francois Bethoux, Theodore R Brown, ..., and Extension Study Investigators

Journal: Multiple Sclerosis Journal

Citation: Multiple Sclerosis Journal 2015, Vol. 21(10) 1322-1331. DOI: 10.1177/1352458514563591

PDF: https://www.researchgate.net/journal/Mul...RG93bmxvYWQifX0

Clinical Question

What are the long-term safety and efficacy profiles of dalfampridine extended release in patients with multiple sclerosis and walking impairment over extended periods (up to 5 years)?

Bottom Line

In open-label extensions of two Phase 3 trials, dalfampridine-ER demonstrated consistent long-term safety and tolerability over up to 5 years with no new safety signals. While overall walking speed declined over time consistent with natural MS disease progression, patients who were responders in the double-blind trials continued to show sustained improvements in walking speed compared with non-responders, and improvements returned within 2 weeks after drug re-initiation.

Major Points

  • Open-label extension studies of MS-F203 and MS-F204 with maximum exposure of 5 years and 3.3 years respectively
  • Total cumulative exposure: 932.6 person-years (MS-F203EXT) and 488.8 person-years (MS-F204EXT)
  • High completion rates: 57.2% (154/269) in MS-F203EXT and 68.2% (146/214) in MS-F204EXT
  • Safety profile consistent with parent trials; no new safety signals emerged
  • Seizure rate 0.8% (4/483 patients), within expected range for MS population (all in patients who received dalfampridine-ER in parent trials)
  • Walking speed improvements lost after discontinuation in parent trial but returned by 2-week assessment after re-initiation
  • Responders from parent trials maintained sustained improvements throughout extensions compared with non-responders
  • Overall decline in walking speed over time consistent with natural MS disease progression (similar to 2-year longitudinal studies)
  • Placebo patients from parent trials showed intermediate improvements when started on dalfampridine-ER (14.7% and 21.7% at 2 weeks)
  • High retention rates even among non-responders: 62.0% and 53.9% (MS-F203EXT), 73.5% and 68.3% (MS-F204EXT)
  • Mean treatment exposure: 39.0 ± 18.73 months (MS-F203EXT) and 26.3 ± 10.1 months (MS-F204EXT)

Design

Study Type: Open-label extension studies of two Phase 3 randomized controlled trials

Randomization:

Blinding: Open-label (unblinded)

Enrollment Period: January 2005 to January 2011 (MS-F203EXT); August 2007 to January 2011 (MS-F204EXT)

Follow-up Duration: Maximum 5 years (MS-F203EXT) and 3.3 years (MS-F204EXT)

Centers: 36

Countries: United States

Sample Size: 483

Analysis: Intention-to-treat analysis. Patients categorized as dalfampridine-ER responders or non-responders based on treatment response in parent double-blind trials. T25FW assessments at 2, 14, and 26 weeks, then every 6 months. Safety follow-up 4 weeks after final on-treatment visit. Average percent change from baseline in walking speed analyzed.

Inclusion Criteria

  • Completed MS-F203 or MS-F204 parent trial
  • Eligible regardless of treatment allocation (dalfampridine-ER or placebo) in parent trial
  • Eligible regardless of treatment response in parent trial
  • Screening performed at or subsequent to final safety follow-up visit of parent study (4 weeks after MS-F203; 2 weeks after MS-F204)
  • Treatment discontinued for at least 2 weeks prior to LTE entry
  • Written informed consent provided

Exclusion Criteria

  • Did not complete parent MS-F203 or MS-F204 trial
  • Use of scheduled corticosteroids, cyclophosphamide, or mitoxantrone not permitted during study
  • Key inclusion/exclusion criteria from parent trials applied (previously published)

Baseline Characteristics

CharacteristicControlActive
NoteNo separate control group; open-label design. Baseline characteristics for overall population:All patients received dalfampridine-ER in open-label extension; characteristics same as overall population
Age (mean ± SD)52.1 ± 8.8 years (MS-F203EXT); 52.0 ± 9.6 years (MS-F204EXT)
Sex - Female67.7% (MS-F203EXT); 67.3% (MS-F204EXT)
Race - White93.3% (MS-F203EXT); 93.9% (MS-F204EXT)
MS type - Secondary progressive52.8% (MS-F203EXT); 50.0% (MS-F204EXT)
MS type - Relapsing-remitting28.3% (MS-F203EXT); 34.6% (MS-F204EXT)
MS type - Primary progressive14.5% (MS-F203EXT); 11.2% (MS-F204EXT)
Disease duration (mean ± SD)170.0 ± 101.0 months (MS-F203EXT); 170.4 ± 110.4 months (MS-F204EXT)
EDSS score (mean ± SD)5.8 ± 1.1 (MS-F203EXT); 5.6 ± 1.1 (MS-F204EXT)
EDSS score (median, range)6.0, range 1.5-7.0 (MS-F203EXT); 6.0, range 2.0-7.0 (MS-F204EXT)
Baseline walking speed2.11 ft/sec (MS-F203EXT); 2.33 ft/sec (MS-F204EXT)

Arms

FieldDalfampridine-ER Open-Label
InterventionAll patients received dalfampridine extended release 10 mg twice daily orally. Immunomodulatory therapies (interferon β-1a, interferon β-1b, glatiramer acetate, natalizumab) allowed if started ≥90 days prior to screening and stable for ≥30 days. Patients stratified by parent trial allocation: placebo (n=68 MS-F203EXT, n=105 MS-F204EXT) or dalfampridine-ER (n=201 MS-F203EXT, n=109 MS-F204EXT), and by responder status from parent trial.
DurationUp to 5 years (MS-F203EXT) or 3.3 years (MS-F204EXT)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Average percent change from baseline in walking speed based on Timed 25-Foot Walk (T25FW). Baseline defined as average walking speed of four pre-treatment visits in parent double-blind studies.PrimaryNon-responders from parent trials showed 6-8% improvement at end of double-blind phase, lost after discontinuation, returned upon re-initiation but remained lower than respondersResponders from parent trials showed ~25% improvement during parent trials, lost after discontinuation, returned by 2-week assessment after re-initiation. Throughout extensions, mean improvement declined but remained higher than non-responders. Overall decline consistent with natural MS disease progression.Not reported for primary walking speed outcome
Treatment-emergent adverse eventsSecondaryN/A (open-label)98.1% (MS-F203EXT); 95.8% (MS-F204EXT)N/AN/A
Serious adverse eventsSecondaryN/A (open-label)34.9% (MS-F203EXT); 18.2% (MS-F204EXT)N/AN/A
Discontinuation due to adverse eventsSecondaryN/A (open-label)13.8% (MS-F203EXT); 3.3% (MS-F204EXT)N/AN/A
DeathsSecondaryN/A (open-label)5 total (4 in MS-F203EXT, 1 in MS-F204EXT); none related to study medicationN/AN/A
SeizuresSecondaryN/A (open-label)4 patients (0.8%); all in patients who received dalfampridine-ER in parent trialsN/AN/A
Walking speed at 8 weeksSecondaryN/A (open-label)Improved by 0.24 ft/sec (MS-F203EXT) and 0.27 ft/sec (MS-F204EXT) from baselineN/AN/A
Walking speed at study endSecondaryN/A (open-label)Similar to or slightly below baseline, but >70% of MS-F203EXT patients at 2 years remained above baselineN/AN/A
Urinary tract infectionAdverseN/A41.6% (MS-F203EXT); 35.0% (MS-F204EXT)N/A
FallAdverseN/A39.8% (MS-F203EXT); 41.1% (MS-F204EXT)N/A
MS relapseAdverseN/A32.3% (MS-F203EXT); 28.5% (MS-F204EXT)N/A
ArthralgiaAdverseN/A24.5% (MS-F203EXT); 15.4% (MS-F204EXT)N/A
Peripheral edemaAdverseN/A19.7% (MS-F203EXT); 17.3% (MS-F204EXT)N/A

Subgroup Analysis

Patients stratified by responder status from parent trials. Responders maintained sustained improvements in walking speed throughout extensions compared with non-responders. Placebo patients from parent trials showed intermediate improvements (14.7% and 21.7% at 2 weeks) between responders and non-responders when initiated on dalfampridine-ER. Retention rates high even among non-responders. Demographic characteristics similar between completers and discontinuers except more females completed MS-F204EXT (73.3% vs 54.4%, p=0.0078).

Criticisms

  • Open-label design; lack of placebo control group limits ability to assess true treatment effect over time
  • Enrollment limited to patients who completed parent trials with specific inclusion/exclusion criteria; may not represent general MS population
  • Self-selected population of patients who tolerate drug and may be more likely to perceive benefit
  • Patients may stay in long-term study for reasons unrelated to treatment (altruism, supporting practitioners)
  • Results may not be generalizable to real-world treatment response or adherence
  • Overall decline in walking speed observed; unclear if this represents disease progression or declining treatment effect
  • Cannot definitively determine if responder status changes over time without long-term placebo-controlled study
  • High attrition rate: 42.8% withdrew from MS-F203EXT, 31.8% from MS-F204EXT
  • Withdrawal of consent was main reason for discontinuation (14.1% and 10.7%)
  • Missing data from discontinued patients could influence group mean walking speed over time
  • Reasons for non-responders remaining in trial not fully understood
  • No assessment of other potential benefits not captured by objective walking measures
  • Follow-up assessments only every 6 months after 26 weeks; may miss fluctuations
  • No laboratory or ECG abnormalities described in detail

Funding

Acorda Therapeutics, Inc.

Based on: Dalfampridine Longterm (Multiple Sclerosis Journal, 2015)

Authors: Andrew D Goodman, Francois Bethoux, Theodore R Brown, ..., and Extension Study Investigators

Citation: Multiple Sclerosis Journal 2015, Vol. 21(10) 1322-1331. DOI: 10.1177/1352458514563591

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