Multiple Sclerosis
Conditions
Keywords
Fampridine
Brief summary
The primary objective is to determine whether prolonged-release fampridine (10 mg twice daily) has a clinically meaningful effect on participant-reported walking ability over a 24-week study period. The secondary objectives are: to determine whether prolonged-release fampridine 10 mg taken twice daily (BID) has a clinically meaningful effect on dynamic and static balance, physical impact of multiple sclerosis (MS), and upper extremity function over a 24-week study period; to evaluate criteria for early assessment of response to fampridine that can predict clinically meaningful benefits in walking ability and balance; to assess the safety and tolerability of prolonged-release fampridine 10 mg twice daily over a 24-week treatment period.
Interventions
DRUGfampridine
DRUGPlacebo
Matched placebo
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must have a diagnosis of primary-progressive, secondary-progressive, progressive-relapsing, or relapsing-remitting MS per revised McDonald Committee criteria \[McDonald 2001; Polman 2005\] as defined by Lublin and Reingold \[Lublin and Reingold 1996\] of at least 3 months duration * Must have an Expanded Disability Status Scale (EDSS) score of 4 to 7, inclusive * Must have walking impairment, as deemed by the Investigator Key
Exclusion criteria
* History of human immunodeficiency virus (HIV) * Presence of acute or chronic hepatitis. Subjects who have evidence of prior hepatitis infection that has been serologically confirmed as resolved are not excluded from study participation * Known allergy to fampridine, pyridine-containing substances, or any of the inactive ingredients in the prolonged-release fampridine tablet * Creatinine clearance (CrCl) of \<80 mL/min * History of malignant disease * Presence of pulmonary disease * A body mass index (BMI) ≥40 (BMI formula: BMI = mass \[kg\]/\[height(m)\]2) NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks | Baseline to 24 weeks | MSWS-12 is a participant self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking. A responder is defined as a participant with a mean improvement of at least 8 points over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. If a participant has a mean MSWS-12 score of \< 0.5 over the double-blind period, and a baseline MSWS-12 score of \< 8 points, the participant is counted as a responder. A participant who indicates they cannot walk at all on MSWS-12 during any double-blind visit, and who shows severe disability and an inability to walk on other efficacy assessments is counted as a non-responder. Estimated proportion obtained from binomial proportions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Timed Up and Go (TUG) Speed Over 24 Weeks | Baseline to Week 24 | TUG is a timed walking test designed to measure gait performance and balance. It measures in seconds the time taken by an individual to stand up from a standard arm chair (approximate seat height of 46 cm \[18in\], arm height 65 cm \[25.6 in\]), walk a distance of 3 meters (118 inches, approximately 10 feet), turn, walk back to the chair, and sit down. A responder is defined as a participant with a mean improvement of at least 15% in TUG speed over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. Estimated proportion obtained from binomial proportions. There are 2 TUG tests given, and the average across the 2 tests is used to calculate average speed. Healthy participants below the age of 79 are expected to complete this task in 7-10 seconds (American College of Rheumatology). Missing data are handled using multiple imputation and baseline is defined as the mean over Screening and Day 1. |
| Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks | Baseline to Week 24 | The 29-item MSIS-29 is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 (no impact of MS) to 100 (extreme impact of MS); a negative change indicates an improvement in function. Data are based on a mixed model for repeated measures (MMRM) model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline MSIS-29 physical score and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1. |
| Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks | Baseline to Week 24 | The BBS is a widely used assessment tool to identify balance impairment. Functional activities such as reaching, bending, transferring, and standing are evaluated on the test to evaluate balance. Participants are asked to complete 14 tasks that are rated from 0 (cannot perform) to 4 (normal performance) for a total of 56 points. BBS scores range from 0 (poor balance) to 56 (good balance); a positive change indicates improvement. Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline BBS and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1. |
| Change From Baseline in ABILHAND Score Over 24 Weeks | Baseline to Week 24 | The ABILHAND Questionnaire measures a participant's perceived difficulty in performing everyday manual activities in the last 3 months. The participant completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 (poor manual ability) to 100 (good manual ability); a positive change indicates an improvement in manual ability. Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline ABILHAND and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the Day 1 assessment. |
Countries
Bulgaria, Czechia, Finland, Italy, Lithuania, Netherlands, Poland, Russia, Serbia, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 646 participants were enrolled. A single site in Poland was later closed due to serious Good Clinical Practice noncompliance issues observed during the conduct of the study. There were 10 participants randomized at this site (6 to fampridine and 4 to placebo). The data from this site were excluded from all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo BID for up to 24 weeks | 319 |
| Fampridine 10 mg BID Prolonged-release fampridine 10 mg BID for up to 24 weeks | 316 |
| Total | 635 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 23 | 21 |
| Overall Study | Consent Withdrawn | 11 | 7 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Investigator Decision | 0 | 1 |
| Overall Study | Lack of Efficacy (Subject Perception) | 10 | 2 |
| Overall Study | Lost to Follow-up | 4 | 2 |
| Overall Study | Other | 5 | 11 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Protocol Violation | 10 | 6 |
Baseline characteristics
| Characteristic | Placebo | Fampridine 10 mg BID | Total |
|---|---|---|---|
| Age, Continuous | 48.8 years STANDARD_DEVIATION 10.5 | 49.0 years STANDARD_DEVIATION 9.82 | 48.9 years STANDARD_DEVIATION 10.16 |
| Sex: Female, Male Female | 181 Participants | 187 Participants | 368 Participants |
| Sex: Female, Male Male | 138 Participants | 129 Participants | 267 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 93 / 319 | 100 / 316 |
| serious Total, serious adverse events | 21 / 319 | 25 / 316 |
Outcome results
Primary
Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks
MSWS-12 is a participant self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking. A responder is defined as a participant with a mean improvement of at least 8 points over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. If a participant has a mean MSWS-12 score of \< 0.5 over the double-blind period, and a baseline MSWS-12 score of \< 8 points, the participant is counted as a responder. A participant who indicates they cannot walk at all on MSWS-12 during any double-blind visit, and who shows severe disability and an inability to walk on other efficacy assessments is counted as a non-responder. Estimated proportion obtained from binomial proportions.
Time frame: Baseline to 24 weeks
Population: Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks | 0.336 proportion of participants |
| Fampridine 10 mg BID | Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks | 0.432 proportion of participants |
Comparison: Based on logistic regression, adjusting for baseline MSWS-12 score, baseline TUG speed, age, screening Expanded Disability Status Scale (EDSS) score and prior aminopyridine. Missing data handled by multiple imputation. Hypothesis testing was performed at the 2-sided 5% significance level overall, with adjustment for testing multiple secondary endpoints.p-value: 0.00695% CI: [1.15, 2.26]Regression, Logistic
Comparison: Based on logistic regression, adjusting for baseline MSWS-12 score, baseline TUG speed, age, screening Expanded Disability Status Scale (EDSS) score and prior aminopyridine. Missing data handled by multiple imputation. Hypothesis testing was performed at the 2-sided 5% significance level overall, with adjustment for testing multiple secondary endpoints.95% CI: [0.03, 0.178]
Comparison: Based on logistic regression, adjusting for baseline MSWS-12 score, baseline TUG speed, age, screening Expanded Disability Status Scale (EDSS) score and prior aminopyridine. Missing data handled by multiple imputation. Hypothesis testing was performed at the 2-sided 5% significance level overall, with adjustment for testing multiple secondary endpoints.95% CI: [1.06, 1.7]
Secondary
Change From Baseline in ABILHAND Score Over 24 Weeks
The ABILHAND Questionnaire measures a participant's perceived difficulty in performing everyday manual activities in the last 3 months. The participant completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 (poor manual ability) to 100 (good manual ability); a positive change indicates an improvement in manual ability. Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline ABILHAND and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the Day 1 assessment.
Time frame: Baseline to Week 24
Population: Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment and available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in ABILHAND Score Over 24 Weeks | 0.75 units on a scale | Standard Error 0.593 |
| Fampridine 10 mg BID | Change From Baseline in ABILHAND Score Over 24 Weeks | 1.49 units on a scale | Standard Error 0.574 |
p-value: 0.19795% CI: [-0.38, 1.86]mixed model for repeated measures
Secondary
Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks
The BBS is a widely used assessment tool to identify balance impairment. Functional activities such as reaching, bending, transferring, and standing are evaluated on the test to evaluate balance. Participants are asked to complete 14 tasks that are rated from 0 (cannot perform) to 4 (normal performance) for a total of 56 points. BBS scores range from 0 (poor balance) to 56 (good balance); a positive change indicates improvement. Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline BBS and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.
Time frame: Baseline to Week 24
Population: Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks | 1.34 units on a scale | Standard Error 0.284 |
| Fampridine 10 mg BID | Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks | 1.75 units on a scale | Standard Error 0.278 |
p-value: 0.14195% CI: [-0.13, 0.95]mixed model for repeated measures
Secondary
Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks
The 29-item MSIS-29 is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 (no impact of MS) to 100 (extreme impact of MS); a negative change indicates an improvement in function. Data are based on a mixed model for repeated measures (MMRM) model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline MSIS-29 physical score and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.
Time frame: Baseline to Week 24
Population: Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks | -4.68 units on a scale | Standard Error 0.936 |
| Fampridine 10 mg BID | Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks | -8.00 units on a scale | Standard Error 0.911 |
p-value: <0.00195% CI: [-5.13, -1.5]mixed model for repeated measures
Secondary
Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Timed Up and Go (TUG) Speed Over 24 Weeks
TUG is a timed walking test designed to measure gait performance and balance. It measures in seconds the time taken by an individual to stand up from a standard arm chair (approximate seat height of 46 cm \[18in\], arm height 65 cm \[25.6 in\]), walk a distance of 3 meters (118 inches, approximately 10 feet), turn, walk back to the chair, and sit down. A responder is defined as a participant with a mean improvement of at least 15% in TUG speed over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. Estimated proportion obtained from binomial proportions. There are 2 TUG tests given, and the average across the 2 tests is used to calculate average speed. Healthy participants below the age of 79 are expected to complete this task in 7-10 seconds (American College of Rheumatology). Missing data are handled using multiple imputation and baseline is defined as the mean over Screening and Day 1.
Time frame: Baseline to Week 24
Population: Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Timed Up and Go (TUG) Speed Over 24 Weeks | 0.347 proportion of participants |
| Fampridine 10 mg BID | Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Timed Up and Go (TUG) Speed Over 24 Weeks | 0.434 proportion of participants |
Comparison: Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.p-value: 0.0395% CI: [1.04, 2.07]Regression, Logistic
Comparison: Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.95% CI: [0.009, 0.175]
Comparison: Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.95% CI: [0.99, 1.51]