Study of Fampridine-ER Tablets in Patients With Multiple... | NCT01328379

Status Module

Label	Type	Description	Intervention Names
Dalfampridine-ER 5mg	Active Comparator	5mg, twice daily	Drug: Dalfampridine-ER 5mg
Dalfampridine-ER 10mg	Active Comparator	10mg, twice daily	Drug: Dalfampridine-ER 10mg
Placebo	Placebo Comparator	placebo, twice daily	Other: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Dalfampridine-ER 5mg	Drug	5mg, twice daily	Dalfampridine-ER 5mg	Fampridine, Dalfampridine, Ampyra

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline in Walking Speed Near Maximum Plasma Concentration at Steady State (CmaxSS) of Placebo and Dalfampridine-ER (5mg and 10mg), Using the Timed 25 Foot Walk (T25FW).	The T25FW test is a quantitative measure of ambulatory function that is widely used by MS specialists to assess the global impact of the disease and its progression on the patient's physical disability. A patient will stand with the toes of his/her shoes on the starting line (identified by a taped mark on the floor) and timing will begin when any part of the patient's foot crosses the tape. Timing will end when any part of the patient's foot crosses the finish line (identified by a taped mark on the floor). Time will be recorded in seconds and rounded to the nearest tenth of a second using a stopwatch provided for this study.	Baseline Visit 1 (double-blind study day 1) and approximately 3-4 hours post dose at Visit 3 (end of double-blind week 4)

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in Walking Speed Near Minimum Plasma Concentration at Steady State (CminSS) of Placebo, Dalfampridine-ER (5mg and 10mg), Using the Timed 25 Foot Walk (T25FW).	The T25FW test is a quantitative measure of ambulatory function that is widely used by MS specialists to assess the global impact of the disease and its progression on the patient's physical disability. A patient will stand with the toes of his/her shoes on the starting line (identified by a taped mark on the floor) and timing will begin when any part of the patient's foot crosses the tape. Timing will end when any part of the patient's foot crosses the finish line (identified by a taped mark on the floor). Time will be recorded in seconds and rounded to the nearest tenth of a second using a stopwatch provided for this study.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Patient has clinically definite Multiple Sclerosis as defined by the MacDonald Criteria.
Patient must be 18 to 70 years of age, inclusive (i.e. on or after their 18th birthday, up to the day before their 71st birthday at the Screening Visit).
Patient who has previously taken Ampyra® or dalfampridine (fampridine or 4 aminopyridine; 4-AP) in any formulation (including compounded), must have withdrawn from the drug for at least one month prior to the Screening Visit.
Patient must be mentally competent to understand and sign the Internal Review Board (IRB)-approved informed consent prior to the performance of any study-specific procedures.
Patient is able to perform all the required study procedures.
In the judgement of the Investigator, the patient has MS-related walking impairment but has sufficient ambulatory ability to be able to complete two trials of the Timed 25 Foot Walk (T25FW) at the screening Visit and every study visit thereafter, with the two trials completed within 5 minutes of one another and in accordance with the specific instructions provided by the National Multiple Sclerosis Society MS Functional Composite Manual.
Patient who is female and of childbearing potential (see Exclusion Criterion 1 for definition) must have a negative urine pregnancy test at the Screening Visit.

Exclusion Criteria:

Patient is a female of childbearing potential (i.e., has not had a hysterectomy or bilateral oophorectomy, or is not at least two years postmenopausal), engaged in active heterosexual relations and is not using one of the following birth control methods: tubal ligation, implantable contraception device, oral, patch or injectable contraceptive, double barrier method, or sexual activity restricted to vasectomized partner.
Patient is pregnant or breastfeeding.
Patient has any history of seizures.
Patient has moderate or severe renal impairment as defined by a calculated creatinine clearance of ≤ 50 mL/minute.
Patient has active urinary tract infection (UTI) at Screening or within the 4 weeks before Screening.
Patient has had an onset (as assessed by the treating physician) of an MS exacerbation within 60 days prior to the Screening Visit.
Patient has started on a concomitant prescription medication regimen within the last three weeks, and/or their concomitant medication regimen is expected to change during the course of the study.
Patient has received cyclophosphamide (Cytoxan) or mitoxantrone (Novantrone) for MS treatment within six months prior to the Screening Visit.
Patient has started a treatment regimen of Betaseron, Avonex, Copaxone, Rebif, Tysabri, Extavia or Gilenya™ within 90 days prior to the Screening Visit or has had any change in the dosing regimen of these drugs within 30 days prior to the Screening Visit.
Patient has received corticosteroids (other than topical preparations) within 30 days prior to the Screening Visit and/or is expected to receive regularly scheduled corticosteroid treatment during the course of the study.
Patient has been administered botulinum toxin in the lower extremities within six months prior to the Screening Visit and/or is expected to receive botulinum toxin in the lower extremities during the course of the study.
Patient has a known allergy to pyridine-containing substances or any of the inactive ingredients of the dalfampridine tablet (colloidal silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide).
Patient has a history of drug or alcohol abuse within the past year.
Patient has clinically significant abnormal laboratory values.
Patient has angina, uncontrolled hypertension, clinically significant cardiac arrhythmias, or any other clinically significant cardiovascular abnormality.
Patient has any medical condition (including psychiatric disease)that would interfere with the interpretation of the study results or the conduct of the study.
Patient has participated in an investigational trial 30 days prior to Screening Visit or plans to enroll in another investigational trial at any time during this study. Non-drug (i.e. observational, registry) and non- medical device trials are allowed.

Contacts/Locations Module

Overall Officials

Name	Affiliation	Role
Andrew R. Blight, PhD	Acorda Therapeutics	Study Director
Mark Agius, MD	University of California, Davis	Principal Investigator
Angela Applebee, MD	University of Vermont Medical Center	Principal Investigator
S. A Azizi, MD, PhD	Temple University Hospital	Principal Investigator
Francois Bethoux, MD	The Cleveland Clinic	Principal Investigator
Christopher Bever, Jr., MD	University of Maryland, Maryland Center for Multiple Sclerosis	Principal Investigator
Eric Borresen, MD	Metrolina Medical Research	Principal Investigator
Aaron Boster, MD	Ohio State University, Columbus	Principal Investigator
Ann Camac, MD	Lahey Clinic	Principal Investigator
Mark Cascione, MD

Facility	Status	City	State	ZIP	Country	Contacts
North Central Neurology Associates, PC		Cullman	Alabama		United States
Phoenix Neurological Associates, Ltd

PubMed Identifier	Type	Citation	Retractions
26565077	Derived	Applebee A, Goodman AD, Mayadev AS, Bethoux F, Goldman MD, Klingler M, Blight AR, Carrazana EJ. Effects of Dalfampridine Extended-release Tablets on 6-minute Walk Distance in Patients With Multiple Sclerosis: A Post Hoc Analysis of a Double-blind, Placebo-controlled Trial. Clin Ther. 2015 Dec 1;37(12):2780-7. doi: 10.1016/j.clinthera.2015.10.014. Epub 2015 Nov 10.
25560174

Results Section

Participant Flow Module

ID	Title	Description
FG000	Placebo	placebo, twice daily
FG001	Dalfampridine-ER 5mg	5mg, twice daily Dalfampridine-ER 5mg: 5mg, twice daily

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Walking Speed Near Maximum Plasma Concentration at Steady State (CmaxSS) of Placebo and Dalfampridine-ER (5mg and 10mg), Using the Timed 25 Foot Walk (T25FW).

The T25FW test is a quantitative measure of ambulatory function that is widely used by MS specialists to assess the global impact of the disease and its progression on the patient's physical disability.

A patient will stand with the toes of his/her shoes on the starting line (identified by a taped mark on the floor) and timing will begin when any part of the patient's foot crosses the tape. Timing will end when any part of the patient's foot crosses the finish line (identified by a taped mark on the floor). Time will be recorded in seconds and rounded to the nearest tenth of a second using a stopwatch provided for this study.

Full Analysis Population (FAP): All randomized patients who took at least one dose of double-blind investigational medication and who have a baseline Timed 25 Foot Walk (T25FW) assessment and at least one post-baseline T25FW assessment.

Posted

Mean

Standard Error

feet per second

Baseline Visit 1 (double-blind study day 1) and approximately 3-4 hours post dose at Visit 3 (end of double-blind week 4)

ID	Title	Description
OG000	Placebo	placebo, twice daily
OG001	Dalfampridine-ER 5mg	5mg, twice daily Dalfampridine-ER 5mg: 5mg, twice daily
OG002	Dalfampridine-ER 10mg	10mg, twice daily Dalfampridine-ER 10mg: 10mg, twice daily

Units	Counts
Participants	OG000136 OG001143 OG002136

Title

Denominators

Categories

Title	Measurements
	OG0000.363± 0.0511 OG0010.423± 0.0470 OG0020.478± 0.0569

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	dalfampridine-ER 5mg twice daily vs. placebo twice daily: Change from baseline in walking speed at Approximately CmaxSS at Visit 3	ANOVA	ANOVA Model: Change from Baseline in Walking Speed - dependent variable and Baseline Walking Speed and Treatment - independent variables	0.457	To demonstrate study sensitivity with respect to efficacy and maintain an overall alpha level ≤ 0.05, a stepwise procedure was performed.	least squares mean	0.054	Standard Error of the Mean	0.0724	2-Sided	95	-0.088	0.196				No	Superiority or Other

Secondary

Change From Baseline in Walking Speed Near Minimum Plasma Concentration at Steady State (CminSS) of Placebo, Dalfampridine-ER (5mg and 10mg), Using the Timed 25 Foot Walk (T25FW).

Full Analysis Population

Posted

Mean

Standard Error

feet per second

Baseline Visit 1 (double-blind study day 1) and approximately 12 hours post dose at Visit 3 (end of double-blind week 4)

ID	Title	Description
OG000	Placebo	placebo, twice daily
OG001	Dalfampridine-ER 5mg	5mg, twice daily Dalfampridine-ER 5mg: 5mg, twice daily
OG002	Dalfampridine-ER 10mg	10mg, twice daily Dalfampridine-ER 10mg: 10mg, twice daily

Secondary

Change From Baseline in 12-item MS Walking Scale (MSWS-12) at Visit 3

The MSWS-12 is a multi-item rating scale that asks patients to rate limitations of their mobility due to MS during the preceding two weeks on a 5-point scale (from 1= not at all to 5=extremely). The scale assesses a range of activities of daily life that rely on walking, such as climbing stairs, moving around the home and walking distances outdoors. The MSWS-12 also addresses the quality of walking, with questions on the smoothness, speed, distance, effort, and mental concentration involved in walking, as well as the need for assistive devices.

For each visit, the MSWS-12 score was calculated by summing the 12 components and transforming into a scale with a range of 0 to 100.

MSWS-12 Score = 100 * [(Sum of Items 1-12) - 12]/48

Full Analysis Population

Posted

Mean

Standard Error

scores on a scale

Baseline Visit 1 (double-blind study day 1) and Visit 3 (end of double-blind week 4)

ID	Title	Description
OG000	Placebo	placebo, twice daily
OG001	Dalfampridine-ER 5mg	5mg, twice daily Dalfampridine-ER 5mg: 5mg, twice daily
OG002	Dalfampridine-ER 10mg	10mg, twice daily Dalfampridine-ER 10mg: 10mg, twice daily

Secondary

Change From Baseline in MSWS-12 at Visit 2

For each visit, the MSWS-12 score was calculated by summing the 12 components and transforming into a scale with a range of 0 to 100.

MSWS-12 Score = 100 * [(Sum of Items 1-12) - 12]/48

Full Analysis Population

Posted

Mean

Standard Error

scores on a scale

Visit 1 (Baseline) and Visit 2 (start of third week double-blind treatment period )

ID	Title	Description
OG000	Placebo	placebo, twice daily
OG001	Dalfampridine-ER 5mg	5mg, twice daily Dalfampridine-ER 5mg: 5mg, twice daily
OG002	Dalfampridine-ER 10mg	10mg, twice daily Dalfampridine-ER 10mg: 10mg, twice daily

Secondary

Change From Baseline in Six-Minute Walk Distance at Visit 2

The Six-Minute Walk, a test of endurance, measures the distance that a patient can walk in a period of 6 minutes. Six-minute walk distance will be reported in feet.

Full Analysis Population

Posted

Mean

Standard Error

Feet

Visit 1 (Baseline) and Visit 2 (start of third week double-blind treatment period )

ID	Title	Description
OG000	Placebo	placebo, twice daily
OG001	Dalfampridine-ER 5mg	5mg, twice daily Dalfampridine-ER 5mg: 5mg, twice daily
OG002	Dalfampridine-ER 10mg	10mg, twice daily Dalfampridine-ER 10mg: 10mg, twice daily

Units	Counts
Participants	OG000

Secondary

Change From Baseline in EuroQol Group 5 Dimensions (EQ-5D) Scores at Visit 3.

Patients completed a brief, generic health status questionnaire: The five specific dimensional scores value patients' health related to mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. Each question has 3 distinguishable choices that can be analyzed using a 3-point scale (i.e. 1 = no problem, 2=some problems and 3= extreme problems).

A response of 1 indicates that the patient has no problem with the dimension tested and a response of 3 indicates that the patient has extreme problems with the dimension tested. For each visit, the average score of 5 dimensions was calculated by averaging the scores of 5 dimensions. EQ-5D final score ranges from 1-3.

Full Analysis Population

Posted

Mean

Standard Error

units on a scale

Baseline Visit 1 (double-blind study day 1) and Visit 3 (end of double-blind week 4)

ID	Title	Description
OG000	Placebo	placebo, twice daily
OG001	Dalfampridine-ER 5mg	5mg, twice daily Dalfampridine-ER 5mg: 5mg, twice daily
OG002	Dalfampridine-ER 10mg	10mg, twice daily Dalfampridine-ER 10mg: 10mg, twice daily

Secondary

Change From Baseline in EQ-5D Visual Analogue Self-rating (VAS) Score at Visit 3.

The EQ-5D is a brief questionnaire that asks patients to rate general state of health. The VAS score rates the general state of health of a patient with 100 for the best imaginable health state and 0 for the worst imaginable health state.

Full Analysis Population. The number of participants analyzed corresponds with number of subjects who completed the questionnaire in each treatment group.

Posted

Mean

Standard Error

units on a scale

Baseline Visit 1 (double-blind study day 1) and Visit 3 (end of double-blind week 4)

ID	Title	Description
OG000	Placebo	placebo, twice daily
OG001	Dalfampridine-ER 5mg	5mg, twice daily Dalfampridine-ER 5mg: 5mg, twice daily
OG002	Dalfampridine-ER 10mg	10mg, twice daily Dalfampridine-ER 10mg: 10mg, twice daily

Units	Counts
Participants

Serious Adverse Events

Term	Organ System	Source Vocabulary	Statistical Information
Breast abscess	Infections and infestations	MedDRA 13.1	EG0000 events0 affected143 at risk EG0011 events1 affected144 at risk EG0020 events0 affected142 at risk
Breast cellulitis	Infections and infestations	MedDRA 13.1	EG0000 events0 affected143 at risk EG0011 events1 affected144 at risk EG0020 events0 affected142 at risk
Loss of consciousness	Nervous system disorders	MedDRA 13.1	EG0000 events0 affected143 at risk EG0010 events0 affected144 at risk EG0021 events1 affected142 at risk
Ovarian adenoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 13.1	EG0000 events0 affected143 at risk EG0010 events0 affected144 at risk EG0021 events1 affected142 at risk
Urosepsis	Infections and infestations	MedDRA 13.1	EG0000 events0 affected143 at risk EG0011 events1 affected144 at risk EG0020 events0 affected142 at risk
Vertigo	Ear and labyrinth disorders	MedDRA 13.1	EG0000 events0 affected143 at risk EG0010 events0 affected144 at risk EG0021 events1 affected142 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Statistical Information
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 13.1	EG0003 events2 affected143 at risk EG0015 events5 affected144 at risk EG0024 events3 affected142 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 13.1	EG0004 events4 affected143 at risk EG0015 events5 affected144 at risk EG0026 events6 affected142 at risk
Balance disorder	Nervous system disorders	MedDRA 13.1	EG0007 events6 affected143 at risk EG0013 events3 affected144 at risk EG0022 events2 affected142 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 13.1	EG0008 events6 affected143 at risk EG0013 events3 affected144 at risk EG0023 events3 affected142 at risk
Dizziness	Nervous system disorders	MedDRA 13.1	EG0003 events3 affected143 at risk EG0017 events7 affected144 at risk EG00217 events15 affected142 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA 13.1	EG0001 events1 affected143 at risk EG0017 events6 affected144 at risk EG0021 events1 affected142 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 13.1	EG0009 events7 affected143 at risk EG00113 events10 affected144 at risk EG0023 events3 affected142 at risk
Fatigue	General disorders	MedDRA 13.1	EG0003 events3 affected143 at risk EG0015 events4 affected144 at risk EG0024 events4 affected142 at risk
Headache	Nervous system disorders	MedDRA 13.1	EG00017 events16 affected143 at risk EG00115 events13 affected144 at risk EG00218 events18 affected142 at risk
Insomnia	Psychiatric disorders	MedDRA 13.1	EG0006 events6 affected143 at risk EG0017 events7 affected144 at risk EG00211 events11 affected142 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 13.1	EG0004 events4 affected143 at risk EG0016 events6 affected144 at risk EG0023 events3 affected142 at risk
Nasopharyngitis	Infections and infestations	MedDRA 13.1	EG0003 events3 affected143 at risk EG0012 events2 affected144 at risk EG0026 events6 affected142 at risk
Nausea	Gastrointestinal disorders	MedDRA 13.1	EG0005 events5 affected143 at risk EG00112 events11 affected144 at risk EG00212 events11 affected142 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 13.1	EG0004 events4 affected143 at risk EG0016 events4 affected144 at risk EG0026 events6 affected142 at risk
Paraesthesia	Nervous system disorders	MedDRA 13.1	EG0004 events4 affected143 at risk EG0012 events2 affected144 at risk EG00212 events7 affected142 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 13.1	EG0002 events1 affected143 at risk EG0015 events5 affected144 at risk EG0023 events3 affected142 at risk
Urinary tract infection	Infections and infestations	MedDRA 13.1	EG0009 events8 affected143 at risk EG0019 events9 affected144 at risk EG00214 events14 affected142 at risk

ID	Term
D020278	Demyelinating Autoimmune Diseases, CNS
D020274	Autoimmune Diseases of the Nervous System
D009422	Nervous System Diseases
D003711	Demyelinating Diseases
D001327	Autoimmune Diseases
D007154	Immune System Diseases

ID	Term
D000631	Aminopyridines
D000588	Amines
D009930	Organic Chemicals
D011725	Pyridines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds

ID	Title	Description
BG000	Placebo	placebo, twice daily
BG001	Dalfampridine-ER 5mg	5mg, twice daily Dalfampridine-ER 5mg: 5mg, twice daily
BG002	Dalfampridine-ER 10mg	10mg, twice daily Dalfampridine-ER 10mg: 10mg, twice daily
BG003	Total	Total of all reporting groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	placebo, twice daily	0	143	77	143
EG001	Dalfampridine-ER 5mg	5mg, twice daily Dalfampridine-ER 5mg: 5mg, twice daily	2	144	80	144
EG002	Dalfampridine-ER 10mg	10mg, twice daily Dalfampridine-ER 10mg: 10mg, twice daily	2	142	84	142