Spinal Muscular Atrophy
Conditions
Keywords
Spinal Muscular Atrophy, 4-aminopyridine, dalfampridine, Ampyra
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.
Interventions
DRUG4-aminopyridine
10 mg/twice daily
DRUGPlacebo
Crossover study involving one trial with sugar pill (placebo)
Sponsors
United States Department of Defense
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. Aged 18 to 50 years at the time of enrollment 2. Have genetically confirmed SMA 3 (homozygous absence of SMN1 exon 7) 3. Ability to walk at least 25 meters without assistance 4. Be free of major orthopedic deformities (i.e. scoliosis, contractures) 5. Normal Cystatin C clearance (\> 80 ml/min)
Exclusion criteria
1. Patients with a history of seizures 2. Patients with any renal impairment 3. Inability to comply with the study procedures 4. Unstable medical illness 5. Any ventilatory assistance 6. Taking experimental medication for SMA other than under this protocol 7. Pregnancy or lactation 8. Menstruating women, not sterilized or not using effective birth control 9. Planning to undergo scoliosis surgery within the next 10 months 10. Inability to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Subjects Includes all subjects who had been consented/enrolled and completed the short term component of the study. | 11 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout (2 Weeks) | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Continuous | 37.7 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 | 0 / 11 | 0 / 10 |
| other Total, other adverse events | 9 / 11 | 4 / 11 | 11 / 11 | 3 / 10 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 | 0 / 11 | 0 / 10 |
Outcome results
Primary
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
Population: Ten of 11 participants completed the long term study. One participant withdrew prior to the long term study due to worsening migraine.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Short Term 4-aminopyridine (Ampyra) | Six Minute Walk Test (6MWT) With Kinematic Evaluation of Gait (Long Term) | 299.10 meters |
| Short Term Placebo | Six Minute Walk Test (6MWT) With Kinematic Evaluation of Gait (Long Term) | 295.20 meters |
Primary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Short Term 4-aminopyridine (Ampyra) | Six Minute Walk Test (6MWT) With Kinematic Evaluation of Gait (Short Term) | 293.05 meters |
| Short Term Placebo | Six Minute Walk Test (6MWT) With Kinematic Evaluation of Gait (Short Term) | 299.50 meters |
Secondary
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
Population: Ten of 11 participants completed the long term study. One participant withdrew prior to the long term study due to worsening migraine.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Short Term 4-aminopyridine (Ampyra) | Hammersmith Functional Motor Scale, Expanded (HFMSE) (Long Term) | 50.90 score |
| Short Term Placebo | Hammersmith Functional Motor Scale, Expanded (HFMSE) (Long Term) | 50.30 score |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Short Term 4-aminopyridine (Ampyra) | Hammersmith Functional Motor Scale, Expanded (HFMSE) (Short Term) | 50.84 score |
| Short Term Placebo | Hammersmith Functional Motor Scale, Expanded (HFMSE) (Short Term) | 50.43 score |
Secondary
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
Population: Ten of 11 participants completed the long term study. One participant withdrew prior to the long term study due to worsening migraine.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Short Term 4-aminopyridine (Ampyra) | Manual Muscle Testing (MMT) Total Score (Long Term) | 177.80 score |
| Short Term Placebo | Manual Muscle Testing (MMT) Total Score (Long Term) | 181.10 score |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Short Term 4-aminopyridine (Ampyra) | Manual Muscle Testing (MMT) Total Score (Short Term) | 181.86 score |
| Short Term Placebo | Manual Muscle Testing (MMT) Total Score (Short Term) | 182.23 score |
Secondary
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
Population: MUNE testing was conducted only during the short term study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Short Term 4-aminopyridine (Ampyra) | Motor Unit Number Estimation (MUNE) | 190.86 motor units |
| Short Term Placebo | Motor Unit Number Estimation (MUNE) | 194.26 motor units |