Short and Long Term Treatment With 4-AP in Ambulatory SMA Patients
- Registration Number
- NCT01645787
- Lead Sponsor
- Columbia University
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 11
- 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)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description 4-aminopyridine (Ampyra) 4-aminopyridine 10 mg tab/ 1 tab twice daily Sugar pill Placebo Placebo 1 tab /twice daily
- Primary Outcome Measures
Name Time Method Six Minute Walk Test (6MWT) With Kinematic Evaluation of Gait (Short Term) Day 14 of each short-term intervention period 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.
Six Minute Walk Test (6MWT) With Kinematic Evaluation of Gait (Long Term) Day 42 of each long-term intervention period 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.
- Secondary Outcome Measures
Name Time Method Hammersmith Functional Motor Scale, Expanded (HFMSE) (Short Term) Day 14 of each short-term intervention period 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.
Hammersmith Functional Motor Scale, Expanded (HFMSE) (Long Term) Day 42 of each long-term intervention period 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.
Manual Muscle Testing (MMT) Total Score (Short Term) Day 14 of each short-term intervention period 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.
Manual Muscle Testing (MMT) Total Score (Long Term) Day 42 of each long-term intervention period 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.
Motor Unit Number Estimation (MUNE) Day 14 of each short-term intervention period 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.
Trial Locations
- Locations (1)
Columbia University Medical Center
🇺🇸New York, New York, United States