Trial Outcomes & Findings for Short and Long Term Treatment With 4-AP in Ambulatory SMA Patients (NCT NCT01645787)

Last Updated: 2024-09-03

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

11 participants

Primary outcome timeframe

Day 14 of each short-term intervention period

Results posted on

2024-09-03

Participant Flow

Participant milestones

Participant milestones
Measure	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).	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).
First Intervention Short Term (2 Weeks) STARTED	6	5
First Intervention Short Term (2 Weeks) COMPLETED	6	5
First Intervention Short Term (2 Weeks) NOT COMPLETED	0	0
Washout (1 Week) STARTED	6	5
Washout (1 Week) COMPLETED	6	5
Washout (1 Week) NOT COMPLETED	0	0
Second Intervention (2 Weeks) STARTED	6	5
Second Intervention (2 Weeks) COMPLETED	6	5
Second Intervention (2 Weeks) NOT COMPLETED	0	0
Washout (2 Weeks) STARTED	5	5
Washout (2 Weeks) COMPLETED	5	5
Washout (2 Weeks) NOT COMPLETED	0	0
Third Intervention Long Term (6 Weeks) STARTED	5	5
Third Intervention Long Term (6 Weeks) COMPLETED	5	5
Third Intervention Long Term (6 Weeks) NOT COMPLETED	0	0
Fourth Intervention (6 Weeks) STARTED	5	5
Fourth Intervention (6 Weeks) COMPLETED	5	5
Fourth Intervention (6 Weeks) NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	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).	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).
Washout (2 Weeks) Adverse Event	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Subjects n=11 Participants Includes all subjects who had been consented/enrolled and completed the short term component of the study.
Age, Continuous	37.7 years n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	9 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 14 of each short-term intervention period

Outcome measures

Outcome measures
Measure	Short Term 4-aminopyridine (Ampyra) n=11 Participants Participants who received 4-aminopyridine 10 mg/twice daily for two weeks.	Short Term Placebo n=11 Participants Participants who received placebo twice daily (matching 4-aminopyridine) for two weeks.
Six Minute Walk Test (6MWT) With Kinematic Evaluation of Gait (Short Term)	293.05 meters Interval 233.6 to 352.5	299.50 meters Interval 240.05 to 358.95

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Short Term 4-aminopyridine (Ampyra) n=10 Participants Participants who received 4-aminopyridine 10 mg/twice daily for two weeks.	Short Term Placebo n=10 Participants Participants who received placebo twice daily (matching 4-aminopyridine) for two weeks.
Six Minute Walk Test (6MWT) With Kinematic Evaluation of Gait (Long Term)	299.10 meters Interval 235.93 to 362.27	295.20 meters Interval 232.03 to 358.37

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Short Term 4-aminopyridine (Ampyra) n=11 Participants Participants who received 4-aminopyridine 10 mg/twice daily for two weeks.	Short Term Placebo n=11 Participants Participants who received placebo twice daily (matching 4-aminopyridine) for two weeks.
Hammersmith Functional Motor Scale, Expanded (HFMSE) (Short Term)	50.84 score Interval 48.53 to 53.16	50.43 score Interval 48.11 to 52.74

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Short Term 4-aminopyridine (Ampyra) n=10 Participants Participants who received 4-aminopyridine 10 mg/twice daily for two weeks.	Short Term Placebo n=10 Participants Participants who received placebo twice daily (matching 4-aminopyridine) for two weeks.
Hammersmith Functional Motor Scale, Expanded (HFMSE) (Long Term)	50.90 score Interval 48.49 to 53.31	50.30 score Interval 47.89 to 52.71

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Short Term 4-aminopyridine (Ampyra) n=11 Participants Participants who received 4-aminopyridine 10 mg/twice daily for two weeks.	Short Term Placebo n=11 Participants Participants who received placebo twice daily (matching 4-aminopyridine) for two weeks.
Manual Muscle Testing (MMT) Total Score (Short Term)	181.86 score Interval 170.5 to 193.23	182.23 score Interval 170.86 to 193.59

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Short Term 4-aminopyridine (Ampyra) n=10 Participants Participants who received 4-aminopyridine 10 mg/twice daily for two weeks.	Short Term Placebo n=10 Participants Participants who received placebo twice daily (matching 4-aminopyridine) for two weeks.
Manual Muscle Testing (MMT) Total Score (Long Term)	177.80 score Interval 163.85 to 191.75	181.10 score Interval 167.15 to 195.05

SECONDARY outcome

Timeframe: Day 14 of each short-term intervention period

Population: MUNE testing was conducted only during the short term study.

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.

Outcome measures

Outcome measures
Measure	Short Term 4-aminopyridine (Ampyra) n=11 Participants Participants who received 4-aminopyridine 10 mg/twice daily for two weeks.	Short Term Placebo n=11 Participants Participants who received placebo twice daily (matching 4-aminopyridine) for two weeks.
Motor Unit Number Estimation (MUNE)	190.86 motor units Interval 142.16 to 239.56	194.26 motor units Interval 145.3 to 243.23

Adverse Events

4-aminopyridine (Short Term)

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Placebo (Short Term)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

4-aminopyridine (Long Term)

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebo (Long Term)

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	4-aminopyridine (Short Term) n=11 participants at risk Participants who received 4-aminopyridine 10 mg/twice daily	Placebo (Short Term) n=11 participants at risk Participants who received placebo (matching 4-aminopyridine) twice daily	4-aminopyridine (Long Term) n=11 participants at risk Participants who received 4-aminopyridine 10 mg/twice daily	Placebo (Long Term) n=10 participants at risk Participants who received placebo (matching 4-aminopyridine) twice daily
Gastrointestinal disorders Upset Stomach	9.1% 1/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/10 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)
General disorders Nausea	0.00% 0/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	9.1% 1/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	10.0% 1/10 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)
General disorders Fall	18.2% 2/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	18.2% 2/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	54.5% 6/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	10.0% 1/10 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)
General disorders Dizziness	27.3% 3/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	18.2% 2/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/10 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)
General disorders Headache/migraine	9.1% 1/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	9.1% 1/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	9.1% 1/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/10 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)
General disorders Tremors	0.00% 0/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	9.1% 1/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/10 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)
Infections and infestations Upper Respiratory Infection (URI)	9.1% 1/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	9.1% 1/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	10.0% 1/10 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)
General disorders Insomnia	9.1% 1/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	18.2% 2/11 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)	0.00% 0/10 • 5 weeks for Short Term study, 16 weeks for Long Term study (up to 21 weeks per participant)

Additional Information

Claudia A. Chiriboga, MD, MPH

Columbia University

Phone: (212) 305-8549

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place