Combination Therapy With Dalfampridine and Locomotor Training for Chronic, Motor Incomplete Spinal Cord Injury

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy, safety, and tolerability of treatment with dalfampridine in combination with locomotor training in persons with chronic, motor incomplete SCI.

Detailed Description
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Research suggests that combining therapies could result in important gains in restoring function and improving quality of life in persons with spinal cord injury (SCI). Locomotor training is an activity-dependent rehabilitation therapy that provides repetitive stepping facilitated by manual assistance and body weight support on a treadmill. Recent studies report improvements in walking and standing in individuals with motor incomplete SCI that have undergone intensive standardized locomotor training therapy. Extended release dalfampridine (also known as fampridine or 4-aminopyridine [4-AP]) is a broad spectrum potassium channel blocker that has been shown in animal studies to increase conduction of action potentials in demyelinated axons. Dalfampridine was recently approved by the U.S. Food and Drug Administration (FDA) as a treatment to improve walking in persons with multiple sclerosis (MS). Demyelination is also a prominent feature of incomplete SCI that contributes to the clinical presentation of persons with these injuries. The purpose of this study is to determine the efficacy, safety, and tolerability of treatment with dalfampridine in combination with locomotor training in persons with chronic, motor incomplete SCI. We hypothesize that persons undergoing combination therapy with dalfampridine and locomotor training will show significantly greater improvements in walking speed and other measures of SCI function than those receiving locomotor training alone.

Official Title
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Restoring Lost Functions After Spinal Cord Injury: Combination Therapy With Dalfampridine and Locomotor Training for Persons With Chronic, Motor Incomplete Spinal Cord Injury

Conditions
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Spinal Cord Injury

Intervention / Treatment
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* Drug: Dalfampridine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 to 70 years, inclusive; Neurological impairment secondary to a traumatic spinal cord injury that occurred at least twelve (12) months prior to the screening visit; Neurological level of the injury between C4 and T10, inclusive; The injury is classified as motor incomplete (AIS grade C or D); Able and willing to comply with the study protocol, including availability for all scheduled clinic visits and locomotor training sessions. Exclusion Criteria: The participant is a lactating female, or a female of childbearing potential who is sexually active, has not had a hysterectomy or oophorectomy, and is not using an approved birth control method (e.g. tubal ligation, implantable contraception device, oral or injectable contraceptive, barrier method, or sexual activity restricted to vasectomized partner); The participant has a history of seizures or treatment for seizure disorders; The participant has renal impairment (Creatinine Clearance < 80 mL/min); The participant has a known allergy to pyridine-containing substances or any of the inactive ingredients of the dalfampridine; The participant has a clinically significant abnormal laboratory values or an abnormal electrocardiogram (ECG); The participant has evidence of significant, diffuse, or generalized lower motor neuron damage; The participant has received new concomitant medication less than 3 weeks before the study or has a dose of current concomitant medication that is expected to change during study; The participant has received botulinum toxin injection for spasticity within 4 months of the screening visit; The participant has taken any other investigational drugs within 30 days before screening; The participant is known to have been treated previously with dalfampridine (4 aminopyridine) in any formulation, whether through participation in a previous fampridine study or by self-medication. The participant has received locomotor training therapy within 6 months of the screening visit; The participant has a history of alcohol or drug abuse in the previous year; The participant has a medical condition that would interfere with interpretation of study results or study conduct. Note: Due to equipment and safety issues associated with locomotor training, participants must weigh less than 300 lbs.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Locomotor Training + Dalfampridine<br>Subjects randomized to this group will undergo 10 weeks of double-blind treatment with extended release dalfampridine tablets (10 mg twice daily) while simultaneously receiving locomotor training therapy (5 sessions per week x 10 weeks = 50 sessions total). | Drug: Dalfampridine<br>* Dalfampridine 10 mg tablet, twice-daily, for 10 weeks<br>* Other names: 4-Aminopyridine (4-AP);|
| Placebo Comparator: Locomotor Training + Placebo<br>Subjects randomized to this group will undergo identical treatment, but will take placebo tablets while simultaneously receiving locomotor training therapy (5 sessions per week x 10 weeks = 50 sessions total). | Drug: Placebo<br>* Placebo tablet, twice daily, for 10 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6-Minute Walk Test (6MWT) Distance at 10 Weeks | The 6MWT measures the distance (in meters) walked within 6 minutes. The test is a measure of endurance; however, can also be used to measure walking speed. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) Visits | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 10-Meter Walk Test (10MWT) Speed at 10 Weeks | The 10MWT measures the time in seconds that it takes a person to walk 10m. The test is a measure of functional capacity and assesses short-duration walking speed. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Timed 25-foot walk (T25FW) Speed at 10 Weeks | The T25FW is a quantitative measure of lower extremity function in persons with multiple sclerosis. The T25FW was the primary outcome measure of efficacy used in MS studies of dalfampridine and is being performed in our study as a means of comparing results across studies and populations. The T25FW can be measured during the 10MWT. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Walking Index for Spinal Cord Injury II (WISCI II) Scores at 10 Weeks | The WISCI II is a walking scale specifically developed for use in clinical trials in persons with incomplete SCI. Walking ability is scored on a 21-point ordinal scale (0-20, where 0 indicates a person is unable to stand and/or participate in assisted walking and 20 indicates a person can walk more than 10m without walking aids or physical assistance), where a lower number indicates higher impairment. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Spinal Cord Injury Functional Ambulation Index (SCI-FAI) Scores at 10 Weeks | The SCI-FAI is an observational gait assessment instrument that addresses three key domains of walking function in individuals with SCI. The three SCI-FAI subscales are Gait, Assistive Device, and Walking Mobility. Parameters of the SCI-FAI are measured during the first 2 minutes of the 6MWT (see above). | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Changes on International Standards for Neurological Classification of Spinal Cord Injury at 10 Weeks | Neurological examination will be performed using the International Standards for Neurological Classification. Sensory scores and lower extremity motor scores are derived at the time of this exam. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Lower-Extremity Motor Scores (LEMS) at 10 Weeks | The LEMS measures strength in five muscle groups bilaterally (hip flexors, knee flexors and extensors, and ankle dorsiflexors) with the modified British Medical Research Council scale and is performed during the International Standards examination. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Berg Balance Scale (BBS) Scores at 10 Weeks | The BBS is a 14-item instrument originally designed to assess the risk for falls in community. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Modified Ashworth Scale (MAS) Scores at 10 Weeks | Spasticity assessments will be performed at each study visit using the modified Ashworth scale (MAS). Ashworth scores will be averaged across three muscle groups bilaterally: hip adductors, knee extensors, and knee flexors. The Ashworth Scale data will be collected on a 1-5 scale rather than the published 0-4 scale. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Bowel Management Questionnaire Scores at 10 Weeks | The bowel management questionnaire uses a 6-point scale and requires the subject to rate the frequency (0, Not at all; 5, Almost always) of ten items regarding bowel management over the past month. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Bladder Management Questionnaire Scores at 10 Weeks | The bladder management questionnaire uses a 6-point scale and requires the subject to rate the frequency (0, Not at all; 5, Always or almost always) of eight items regarding bladder management over the past month. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Female Sexual Function Index (FSFI) Scores at 10 Weeks | The FSFI is a multidimensional, self-report instrument used to assess female sexual function. Six domains are identified that include desire, subjective arousal, lubrication, orgasm, sexual satisfaction, and pain. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in International Index of Erectile Function (IIEF) Scores at 10 Weeks | The IIEF is a 15-item questionnaire to assess male sexual function. Quality of male sexual function is assessed in 5 domains, with 6 items that assess erectile function, 2 items that address orgasmic function, 2 questions that assess sexual desire, 3 items that assess intercourse satisfaction, and 2 items that assess overall sexual satisfaction. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Changes in Pulmonary Function Tests at 10 Weeks | Pulmonary function testing will be performed (V max Spectra 29N, Carefusion, Yorba Linda, CA) to measure spirometric parameters, static lung volumes, cough strength, and maximal mouth expiratory and inspiratory pressures. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Changes in Autonomic Function at 10 Weeks | To assess changes in autonomic cardiovascular function, heart rate (3 lead ECG Ivy Biomedical Systems, Inc. Branford, CT) and blood pressure (Finometer Midi, Finapres Medical Systems, Amsterdam, Netherlands) will be continuously monitored at 5 minute intervals at rest and during locomotor training. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Changes on the International Spinal Cord Injury Pain Basic Data Set (ISCIPDS:B) at 10 Weeks | The ISCIPDS:B contains core questions about clinically relevant information concerning SCI-related pain that can be collected by health-care professionals with expertise in SCI in various clinical settings. Each person is asked to describe the three worst pain problems he/she is currently experiencing. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Spinal Cord Independence Measure III (SCIM III) Scores at 10 Weeks | The SCIM is a measure of functional ability developed specifically for individuals with SCI to evaluate their performance of activities of daily living (ADL). The SCIM III is composed of 19 items in 3 sub-scales: (a) self-care (6 items, sub-score 0-20); (b) respiration and sphincter management (4 items, sub-score 0-40); and (c) mobility (9 items, sub-score 0-40). The total score ranges from 0 to 100. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Spinal Cord Injury-Functional Index (SCI-FI) Scores at 10 Weeks | The Spinal Cord Injury Functional Index (SCI-FI) is a comprehensive, SCI-specific measure to assess functional activities related to quality of life for individuals with SCI. The SCI-FI covers five distinct functional domains: Ambulation, Basic Mobility, Fine Motor Function, Self-Care (including bowel and bladder), and Wheeled Mobility. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in 12-Item Short Form Health Survey (SF-12) Scores at 10 Weeks | The SF-12 is a generic health-status measure developed by RAND to assess outcomes of medical care and has been used previously by the SCI Model Systems. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Satisfaction with Life Scale (SWLS) Scores at 10 Weeks | The SWLS is a 5-item measure of the single concept of global life satisfaction. The SWLS is currently used in the SCI Model Systems dataset and normative data for individuals with SCI is available. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Craig Handicap Assessment and Reporting Technique (CHART) Scores at 10 Weeks | The CHART is a 32-item self-report measure of major domains of participation, which has also been utilized extensively by SCI Model System researchers. It assesses functioning in 6 domains of normative role functioning: Physical Independence, Mobility, Occupation, Social Integration, Cognitive Independence, & Economic Self-Sufficiency. | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Subject Global Impression (SGI) of Change at 10 Weeks | The SGI of change is a subject-rated instrument that measures change in the subject's overall status on a 7-point scale. Scores range from 1 (very much improved) to 7 (very much worse). | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Change in Clinician Global Impression (CGI) of Change at 10 Weeks | The study physician will rate on a 7-point scale the subject's overall clinical condition following treatment as compared to that at baseline. Scores range from 1 (very much improved) to 7 (very much worse). | Baseline, Mid-Point (Week 5), Final (Week 10), and Follow-up (Week 22) | 
| Adverse Event Case Report Form | Adverse experience(s) will be recorded on the Adverse Event Case Report Form, including the date and time of onset, severity, the relationship to study intervention, the date of resolution, the action taken, and the outcome of the adverse experience. The responsible physician will make a causality assessment for every adverse experience. | Every two weeks for 10 weeks | 
| Side Effects Record | Participants will be provided a list of side-effects associated with dalfampridine treatment. Three lines marked other for open-choice responses will accompany the selection of options for forced-choice side-effects. Participants will rate the severity (visual analog scale [VAS]; 0-100) and frequency (never, occasionally, sometimes, often or always) of side effects for each of the forced and open choice answers. Severity and frequency of side-effects will be rated by participants every 2 weeks during the intervention part of the study. | Every two weeks for 10 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal Cord Injuries, 4-Aminopyridine, Physical Therapy Modalities, Randomized Controlled Trial, Rehabilitation, Walking