Short and Long Term Treatment With 4-AP in Ambulatory SMA Patients

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.

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.

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.

MMT will involve pushing and pulling against the evaluators hand (MMT) and HHD will involve pushing or pulling as against a handheld measuring device. The purpose of these tests is to measure the strength in different muscles. The MMT involves testing fourteen muscle groups of the arm and leg on both sides of the body. The evaluator will alternate sides between tests. The measuring device will be used on 10 muscle groups on both sides of the body.

Motor Unit Number Estimation (MUNE) is a noninvasive test that identifies the number of surviving 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 your right arm and leg while recording the response over a muscle innervated by each nerve.

Inclusion Criteria: Aged 18 to 50 years at the time of enrollment Have genetically confirmed SMA 3 (homozygous absence of SMN1 exon 7) Ability to walk at least 25 meters without assistance Be free of major orthopedic deformities (i.e. scoliosis, contractures) Normal Cystatin C clearance (> 80 ml/min) Exclusion Criteria: Patients with a history of seizures Patients with any renal impairment Inability to comply with the study procedures Unstable medical illness Any ventilatory assistance Taking experimental medication for SMA other than under this protocol Pregnancy or lactation Menstruating women, not sterilized or not using effective birth control Planning to undergo scoliosis surgery within the next 10 months Inability to give informed consent