ENHANCE: Efficacy and Safety Study of Prolonged-Release Fampridine in Participants With Multiple Sclerosis

• Sponsor: Biogen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02219932
• Collaborator: (none)
• Enrollment: 646
• Locations: 87
• Arms: 2
• Duration (Months): 17
• Patients Per Site: 7.4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: fampridine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 646 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Study to Assess the Long-Term Efficacy and Safety of Prolonged Release Fampridine (BIIB041) 10 mg, Administered Twice Daily in Subjects With Multiple Sclerosis (ENHANCE)
• Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Feb 1, 2016
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fampridine 10 mg BID Prolonged-release fampridine 10 mg twice daily (BID) for up to 24 weeks	Drug: fampridine; Other Names: dalfampridine Ampyra Fampyra fampridine prolonged-release tablets BIIB041
Placebo Comparator: Placebo Matched placebo 10 mg BID for up to 24 weeks	Drug: Placebo; Matched placebo

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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/Exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research site	Cullman	Alabama	United States	35058
2	Research site	Phoenix	Arizona	United States	85013
3	Research site	San Diego	California	United States	92108
4	Research site	Bradenton	Florida	United States	34205
5	Research Site	Orlando	Florida	United States	32806
6	Research site	Tampa	Florida	United States	33612
7	Research site	Tampa	Florida	United States	33634
8	Research site	West Palm Beach	Florida	United States	33407
9	Research site	Lexington	Kentucky	United States	40513
10	Research site	New Bedford	Massachusetts	United States	02740
11	Research site	Detroit	Michigan	United States	48201
12	Research site	Chesterfield	Missouri	United States	63017
13	Research site	Rochester	New York	United States	14642
14	Research site	Charlotte	North Carolina	United States	28207
15	Research site	Charlotte	North Carolina	United States	28210
16	Research site	Columbus	Ohio	United States	43210
17	Research site	Roanoke	Virginia	United States	24018
18	Research site	Pleven		Bulgaria	5800
19	Research site	Plovdiv		Bulgaria	4002
20	Research site	Sofia		Bulgaria	1113
21	Research site	Sofia		Bulgaria	1142
22	Research Site	Sofia		Bulgaria	1407
23	Research site	Sofia		Bulgaria	1431
24	Research site	Sofia		Bulgaria	1606
25	Research Site	Sofia		Bulgaria	1797
26	Research site	Brno		Czech Republic	62500
27	Research site	Brno		Czech Republic	65691
28	Research site	Chocen		Czech Republic	56501
29	Research site	Havirov		Czech Republic	73601
30	Research site	Jihlava		Czech Republic	58633
31	Research site	Pardubice		Czech Republic	53203
32	Research site	Praha 2		Czech Republic	12808
33	Research site	Praha 5		Czech Republic	15006
34	Research site	Teplice		Czech Republic	41501
35	Research site	Helsinki		Finland	00100
36	Research site	Oulu		Finland	90220
37	Research site	Tampere		Finland	33520
38	Research site	Turku		Finland	20520
39	Research Site	Gallarate		Italy
40	Research site	Messina		Italy	98121
41	Research site	Milano		Italy	20133
42	Research site	Napoli		Italy	80138
43	Research site	Rome		Italy	00189
44	Research site	Kaunas		Lithuania	50009
45	Research site	Klaipeda		Lithuania	92288
46	Research site	Vilnius		Lithuania	08661
47	Research Site	Breda		Netherlands	4818
48	Research Site	s-Hertogenbosch		Netherlands	5223
49	Research Site	Sittard-Geleen		Netherlands	6162
50	Research Site	Bialystok		Poland	15-276
51	Research site	Gdansk		Poland	80-803
52	Research site	Grudziadz		Poland	86-300
53	Research Site	Katowice		Poland	40-595
54	Research Site	Katowice		Poland	40-749
55	Research site	Katowice		Poland	40-752
56	Research Site	Kielce		Poland	25-726
57	Research site	Krakow		Poland	31-505
58	Research site	Krakow		Poland	31-637
59	Research site	Lodz		Poland	90-324
60	Research site	Olsztyn		Poland	10-561
61	Research site	Plewiska		Poland	62064
62	Research site	Rzeszow		Poland	35055
63	Research site	Warsaw		Poland	00-669
64	Research site	Warsaw		Poland	01-697
65	Research site	Warsaw		Poland	04-749
66	Research Site	Kazan		Russian Federation	420021
67	Research site	Kemerovo		Russian Federation	650066
68	Research site	Krasnoyarsk		Russian Federation	660037
69	Research Site	Moscow		Russian Federation	127015
70	Research site	Moscow		Russian Federation	129128
71	Research Site	Nizhny Novgorod		Russian Federation	60155
72	Research site	Belgrade		Serbia	11000
73	Research site	Kragujevac		Serbia	34000
74	Research site	Nis		Serbia	18000
75	Research site	Exeter	Devon	United Kingdom	EX2 5DW
76	Research site	Plymouth	Devon	United Kingdom	PL6 8DH
77	Research site	Romford	Essex	United Kingdom	RM7 0AG
78	Research site	Salford	Greater Manchester	United Kingdom	M6 8HD
79	Research site	Norwich	Norfolk	United Kingdom	NR4 7UY
80	Research site	Glasgow	Scotland	United Kingdom	G51 4TF
81	Research site	Chertsey	Surrey	United Kingdom	KT16 0PZ
82	Research site	Cardiff	Swansea	United Kingdom	SA6 6NL
83	Research site	Birmingham	West Midlands	United Kingdom	B15 2WB
84	Research site	London		United Kingdom	E1 2AT
85	Research site	London		United Kingdom	NW3 2QG
86	Research site	London		United Kingdom	WC1N 3BG
87	Research site	Nottingham		United Kingdom	NG7 2UH

Sponsors and Collaborators

• Biogen

Investigators

• Study Director: Medical Director, Biogen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT02219932
• Other Study ID Numbers: 218MS305; 2013-003600-40
• First Posted: Aug 19, 2014
• Last Update Posted: Mar 27, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by Biogen: Fampridine
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; 4-Aminopyridine

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Placebo	Fampridine 10 mg BID
Arm/Group Description	Placebo twice daily (BID) for up to 24 weeks	Prolonged-release fampridine 10 mg BID for up to 24 weeks
Period Title: Overall Study
STARTED	319	317
Randomized, Not Treated	0	1
COMPLETED	254	266
NOT COMPLETED	65	51

Baseline Characteristics

Arm/Group Title	Placebo	Fampridine 10 mg BID	Total
Arm/Group Description	Placebo BID for up to 24 weeks	Prolonged-release fampridine 10 mg BID for up to 24 weeks	Total of all reporting groups
Overall Participants	319	316	635
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.8 (10.50)	49.0 (9.82)	48.9 (10.16)
Sex: Female, Male (Count of Participants)
Female	181 56.7%	187 59.2%	368 58%
Male	138 43.3%	129 40.8%	267 42%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.

Arm/Group Title	Placebo	Fampridine 10 mg BID
Arm/Group Description	Placebo BID for up to 24 weeks	Prolonged-release fampridine 10 mg BID for up to 24 weeks
Measure Participants	318	315
Number [proportion of participants]	0.336 0.1%	0.432 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fampridine 10 mg BID
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 1.15 to 2.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	fampridine vs. placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fampridine 10 mg BID
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference for Adjusted Proportions
	Estimated Value	0.104
	Confidence Interval	(2-Sided) 95%; 0.030 to 0.178
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fampridine 10 mg BID
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 95%; 1.06 to 1.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Timed Up and Go (TUG) Speed Over 24 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.

Arm/Group Title	Placebo	Fampridine 10 mg BID
Arm/Group Description	Placebo BID for up to 24 weeks	Prolonged-release fampridine 10 mg BID for up to 24 weeks
Measure Participants	318	315
Number [proportion of participants]	0.347 0.1%	0.434 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fampridine 10 mg BID
	Comments	Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; 1.04 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fampridine 10 mg BID
	Comments	Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference for Adjusted Proportions
	Estimated Value	0.092
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.175
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fampridine 10 mg BID
	Comments	Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 95%; 0.99 to 1.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.

Arm/Group Title	Placebo	Fampridine 10 mg BID
Arm/Group Description	Placebo BID for up to 24 weeks	Prolonged-release fampridine 10 mg BID for up to 24 weeks
Measure Participants	318	315
Least Squares Mean (Standard Error) [units on a scale]	-4.68 (0.936)	-8.00 (0.911)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fampridine 10 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.31
	Confidence Interval	(2-Sided) 95%; -5.13 to -1.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.925
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.

Arm/Group Title	Placebo	Fampridine 10 mg BID
Arm/Group Description	Placebo BID for up to 24 weeks	Prolonged-release fampridine 10 mg BID for up to 24 weeks
Measure Participants	318	315
Least Squares Mean (Standard Error) [units on a scale]	1.34 (0.284)	1.75 (0.278)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fampridine 10 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.141
	Comments
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.277
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in ABILHAND Score Over 24 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Fampridine 10 mg BID
Arm/Group Description	Placebo BID for up to 24 weeks	Prolonged-release fampridine 10 mg BID for up to 24 weeks
Measure Participants	315	312
Least Squares Mean (Standard Error) [units on a scale]	0.75 (0.593)	1.49 (0.574)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fampridine 10 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.197
	Comments
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; -0.38 to 1.86
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.573
	Estimation Comments

Adverse Events

Time Frame	Collected through follow-up (14 [±3] days following Week 24/Early Termination). Serious adverse events collected from signing of informed consent; adverse events collected from first dose of study treatment.
Arm/Group Title	Placebo		Fampridine 10mg BID
Arm/Group Description	Placebo twice daily (BID) for up to 24 weeks		Prolonged-release fampridine 10 mg BID for up to 24 weeks
All Cause Mortality
	Placebo		Fampridine 10mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Fampridine 10mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/319 (6.6%)		25/316 (7.9%)
Cardiac disorders
Acute myocardial infarction	1/319 (0.3%)		0/316 (0%)
Atrioventricular block second degree	1/319 (0.3%)		0/316 (0%)
Coronary artery stenosis	0/319 (0%)		1/316 (0.3%)
Ear and labyrinth disorders
Vertigo positional	0/319 (0%)		1/316 (0.3%)
General disorders
Chest pain	0/319 (0%)		1/316 (0.3%)
Infections and infestations
Diverticulitis	0/319 (0%)		1/316 (0.3%)
Gallbladder empyema	0/319 (0%)		1/316 (0.3%)
Injection site infection	1/319 (0.3%)		0/316 (0%)
Urinary tract infection	1/319 (0.3%)		2/316 (0.6%)
Injury, poisoning and procedural complications
Ankle fracture	1/319 (0.3%)		0/316 (0%)
Fall	2/319 (0.6%)		2/316 (0.6%)
Femur fracture	1/319 (0.3%)		0/316 (0%)
Humerus fracture	0/319 (0%)		1/316 (0.3%)
Joint dislocation	0/319 (0%)		1/316 (0.3%)
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder	1/319 (0.3%)		0/316 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/319 (0%)		1/316 (0.3%)
Breast cancer	0/319 (0%)		1/316 (0.3%)
Ovarian endometrioid carcinoma	1/319 (0.3%)		0/316 (0%)
Uterine leiomyoma	0/319 (0%)		1/316 (0.3%)
Nervous system disorders
Dizziness	1/319 (0.3%)		0/316 (0%)
Multiple sclerosis relapse	10/319 (3.1%)		14/316 (4.4%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/319 (0.3%)		0/316 (0%)
Psychiatric disorders
Anxiety	1/319 (0.3%)		0/316 (0%)
Mental disorder	1/319 (0.3%)		0/316 (0%)
Reproductive system and breast disorders
Endometrial atrophy	1/319 (0.3%)		0/316 (0%)
Metrorrhagia	1/319 (0.3%)		0/316 (0%)
Vascular disorders
Peripheral ischaemia	0/319 (0%)		1/316 (0.3%)
Other (Not Including Serious) Adverse Events
	Placebo		Fampridine 10mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/319 (29.2%)		100/316 (31.6%)
Infections and infestations
Nasopharyngitis	18/319 (5.6%)		15/316 (4.7%)
Urinary tract infection	29/319 (9.1%)		40/316 (12.7%)
Injury, poisoning and procedural complications
Fall	17/319 (5.3%)		22/316 (7%)
Musculoskeletal and connective tissue disorders
Back pain	11/319 (3.4%)		16/316 (5.1%)
Nervous system disorders
Multiple sclerosis relapse	31/319 (9.7%)		31/316 (9.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.