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| Name | Class |
|---|---|
| United States Department of Defense | FED |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 4-aminopyridine (Ampyra) | Active Comparator | 10 mg tab/ 1 tab twice daily |
|
| Sugar pill | Placebo Comparator | Placebo 1 tab /twice daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 4-aminopyridine | Drug | 10 mg/twice daily |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | Day 42 of each long-term intervention period |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Claudia A. Chiriboga, MD, MPH | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Columbia University Medical Center | New York | New York | 10032 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | 4-aminopyridine, Then Placebo | Participants first received 4-aminopyridine 10 mg/twice daily for two weeks. After a washout period of one week, they then received placebo tablet (matching 4-aminopyridine) twice daily for two weeks (short term study). After a washout period of two weeks (following short term study), participants received 4-aminopyridine 10 mg/twice daily for six weeks. After a washout period of two weeks, they then received placebo tablet (matching 4-aminopyridine) twice daily for six weeks (long term study). |
| FG001 | Placebo, Then 4-aminopyridine | Participants first received placebo tablet (matching 4-aminopyridine) twice daily for two weeks. After a washout period of one week, they then received 4-aminopyridine 10 mg/twice daily for two weeks (short term study). After a washout period of two weeks (following short term study), participants first received placebo tablet (matching 4-aminopyridine) twice daily for six weeks. After a washout period of two weeks, they then received 4-aminopyridine 10 mg/twice daily for six weeks (long term study). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention Short Term (2 Weeks) |
| |||||||||||||
| Washout (1 Week) |
| |||||||||||||
| Second Intervention (2 Weeks) |
| |||||||||||||
| Washout (2 Weeks) |
| |||||||||||||
| Third Intervention Long Term (6 Weeks) |
| |||||||||||||
| Washout (2 Weeks) |
| |||||||||||||
| Fourth Intervention (6 Weeks) |
|
A total of 11 subjects have thus been consented/enrolled in the study: 11 completed the short term component and 10 completed the long term components, a figure corresponding to the original targeted complement of the long term component.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Subjects | Includes all subjects who had been consented/enrolled and completed the short term component of the study. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | 90% Confidence Interval | meters | Day 14 of each short-term intervention period |
|
5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 4-aminopyridine (Short Term) | Participants who received 4-aminopyridine 10 mg/twice daily |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upset Stomach | Gastrointestinal disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Claudia A. Chiriboga, MD, MPH | Columbia University | (212) 305-8549 | cac3@columbia.edu |
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| ID | Term |
|---|---|
| D009134 | Muscular Atrophy, Spinal |
| ID | Term |
|---|---|
| D013118 | Spinal Cord Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D016472 | Motor Neuron Disease |
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| ID | Term |
|---|---|
| D015761 | 4-Aminopyridine |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D000631 | Aminopyridines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D011725 | Pyridines |
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| Placebo | Drug | Crossover study involving one trial with sugar pill (placebo) |
|
|
| Day 14 of each short-term intervention period |
| 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. | 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. | 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. | 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. | Day 14 of each short-term intervention period |
| NOT COMPLETED |
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| NOT COMPLETED |
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| NOT COMPLETED |
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|
| NOT COMPLETED |
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| NOT COMPLETED |
|
| NOT COMPLETED |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 |
| Short Term Placebo |
Participants who received placebo twice daily (matching 4-aminopyridine) for two weeks. |
|
|
| 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. | Ten of 11 participants completed the long term study. One participant withdrew prior to the long term study due to worsening migraine. | Posted | Mean | 90% Confidence Interval | meters | Day 42 of each long-term intervention period |
|
|
|
| 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. | Posted | Mean | 90% Confidence Interval | score | Day 14 of each short-term intervention period |
|
|
|
| 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. | Ten of 11 participants completed the long term study. One participant withdrew prior to the long term study due to worsening migraine. | Posted | Mean | 90% Confidence Interval | score | Day 42 of each long-term intervention period |
|
|
|
| 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. | Posted | Mean | 90% Confidence Interval | score | Day 14 of each short-term intervention period |
|
|
|
| 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. | Ten of 11 participants completed the long term study. One participant withdrew prior to the long term study due to worsening migraine. | Posted | Mean | 90% Confidence Interval | score | Day 42 of each long-term intervention period |
|
|
|
| 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. | MUNE testing was conducted only during the short term study. | Posted | Mean | 90% Confidence Interval | motor units | Day 14 of each short-term intervention period |
|
|
|
| 0 |
| 11 |
| 0 |
| 11 |
| 9 |
| 11 |
| EG001 | Placebo (Short Term) | Participants who received placebo (matching 4-aminopyridine) twice daily | 0 | 11 | 0 | 11 | 4 | 11 |
| EG002 | 4-aminopyridine (Long Term) | Participants who received 4-aminopyridine 10 mg/twice daily | 0 | 11 | 0 | 11 | 11 | 11 |
| EG003 | Placebo (Long Term) | Participants who received placebo (matching 4-aminopyridine) twice daily | 0 | 10 | 0 | 10 | 3 | 10 |
| Nausea | General disorders | Non-systematic Assessment |
|
| Fall | General disorders | Non-systematic Assessment |
|
| Dizziness | General disorders | Non-systematic Assessment |
|
| Headache/migraine | General disorders | Non-systematic Assessment |
|
| Tremors | General disorders | Non-systematic Assessment |
|
| Upper Respiratory Infection (URI) | Infections and infestations | Non-systematic Assessment |
|
| Insomnia | General disorders | Non-systematic Assessment |
|
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| D019636 | Neurodegenerative Diseases |
| D009468 | Neuromuscular Diseases |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D002241 | Carbohydrates |