The purpose of this study is to assess whether 4-AP (Dalfampridine-ER, Ampyra) improves walking ability and endurance in adult patients with Spinal muscular atrophy (SMA) Type 3 compared to placebo and whether the duration of treatment affects outcome.
Spinal muscular atrophy (SMA) is a genetically determined neuromuscular disorder that results in muscle weakness and impaired functional mobility. Fatigue is a common symptom in SMA with a resultant impact on physical function and quality of life however the precise mechanisms are unknown. At present there is no treatment for SMA. There is evidence that 4-AP improves function in SMA animal models. In patients with multiple sclerosis, 4-AP was found to improve walking ability and diminish fatigue. The purpose of the study is to determine whether treatment with 4-AP is associated with an increase in walking speed and endurance compared to placebo and whether the duration of treatment affects outcome. The study comprises a short term treatment trial in which participants are treated for 2 weeks with 4-AP and placebo in random sequence followed by a long treatment trial of 6 weeks in which patients are also treated with placebo and 4 AP. The primary outcome measure of the clinical study will be the six minute walk test (6MWT), which has been documented to be a valid and sensitive instrument to identify fatigue among ambulatory SMA patients. We will also assess the effect of 4-AP on muscle and nerve electrical function via electromyography (EMG) during the short term trial. Results of this study may provide support for larger clinical trials.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
11
10 mg/twice daily
Crossover study involving one trial with sugar pill (placebo)
Columbia University Medical Center
New York, New York, United States
Six Minute Walk Test (6MWT) With Kinematic Evaluation of Gait (Short Term)
The primary outcome measure will be distance walked in the 6MWT. This measure is an objective evaluation of functional capacity which measures the distance a person can walk quickly in six minutes and is most representative of a person's ability because the test intensity is self-selected. The 6MWT can be safely performed in ambulatory SMA patients and correlates with standard SMA outcome measures including timed walking tests. In SMA, the 6MWT may be more sensitive to clinically meaningful changes in patients with type 3 SMA as it is a direct measure of their functional mobility.
Time frame: Day 14 of each short-term intervention period
Six Minute Walk Test (6MWT) With Kinematic Evaluation of Gait (Long Term)
The primary outcome measure will be distance walked in the 6MWT. This measure is an objective evaluation of functional capacity which measures the distance a person can walk quickly in six minutes and is most representative of a person's ability because the test intensity is self-selected. The 6MWT can be safely performed in ambulatory SMA patients and correlates with standard SMA outcome measures including timed walking tests. In SMA, the 6MWT may be more sensitive to clinically meaningful changes in patients with type 3 SMA as it is a direct measure of their functional mobility.
Time frame: Day 42 of each long-term intervention period
Hammersmith Functional Motor Scale, Expanded (HFMSE) (Short Term)
Assessments of motor function are clinically relevant and are a good adjunct to tests of walking ability. The HFMSE, a 33-item scale designed for SMA type 2 and 3 patients, and is associated with minimal patient burden requiring only standard equipment and is completed on average in less than 15 minutes. The HFMSE showed good test-retest reliability and is correlated with other clinical and physiological measures in SMA. The score range is 0 (all items failed) to 66 (all items achieved unaided), with higher score indicating higher level of motor function.
Time frame: Day 14 of each short-term intervention period
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Hammersmith Functional Motor Scale, Expanded (HFMSE) (Long Term)
Assessments of motor function are clinically relevant and are a good adjunct to tests of walking ability. The HFMSE, a 33-item scale designed for SMA type 2 and 3 patients, and is associated with minimal patient burden requiring only standard equipment and is completed on average in less than 15 minutes. The HFMSE showed good test-retest reliability and is correlated with other clinical and physiological measures in SMA. The score range is 0 (all items failed) to 66 (all items achieved unaided), with higher score indicating higher level of motor function.
Time frame: Day 42 of each long-term intervention period
Manual Muscle Testing (MMT) Total Score (Short Term)
MMT will involve pushing and pulling against the evaluators hand (MMT). The purpose of this test is to measure the strength in different muscles. MMT was performed on 28 muscle groups (8 muscle groups on each leg and 6 muscle groups on each arm), including proximal and distal musculature. The score range for each muscle group is 0 to 10, with a higher score indicating better muscle strength. The total score range is 0 to 280.
Time frame: Day 14 of each short-term intervention period
Manual Muscle Testing (MMT) Total Score (Long Term)
MMT will involve pushing and pulling against the evaluators hand (MMT). The purpose of this test is to measure the strength in different muscles. MMT was performed on 28 muscle groups (8 muscle groups on each leg and 6 muscle groups on each arm), including proximal and distal musculature. The score range for each muscle group is 0 to 10, with a higher score indicating better muscle strength. The total score range is 0 to 280.
Time frame: Day 42 of each long-term intervention period
Motor Unit Number Estimation (MUNE)
Motor Unit Number Estimation (MUNE) is a noninvasive test that identifies the number of motor units (motor nerve cells and the territory of muscle fibers they control) using electrical muscle stimulation and recording the response. The nerve conduction study involves the administration of modest electrical stimulations (pulsations or throbbing sensations from low level electricity) to a total of 4 nerves in the right arm and leg while recording the response over a muscle innervated by each nerve. MUNE is calculated by determining the compound motor action potential (CMAP) amplitude or area under the curve of a distal muscle in response to supramaximal stimulation, and then dividing the result by the amplitude or area under the curve of a single motor unit action potential.
Time frame: Day 14 of each short-term intervention period