Amyotrophic Lateral Sclerosis
Conditions
Keywords
Amyotrophic Lateral Sclerosis, ALS, Lou Gehrig
Brief summary
This study evaluates the effect of retigabine (600 mg/day, 900 mg/day, or placebo) on motor neuron activity in people with Amyotrophic Lateral Sclerosis (ALS). The total study duration is approximately 14 weeks. ALS subjects will take study drug for approximately 10 weeks.
Detailed description
One of the major disease features of ALS is the progressive death of motor neurons. Human, rodent and stem cell-based model studies support the hypothesis that neuronal hyperexcitability may contribute to neurodegeneration in both sporadic and familial ALS. The investigators are doing this research study to find out whether retigabine will reduce motor neuron excitability in people with ALS. the investigators will also determine whether the drug is tolerable and safe for patients with ALS. The proposed study will determine how the potassium channel opener ezogabine (retigabine) affects neurophysiological measures of upper and lower motor neuron excitability in ALS patients as assessed by transcranial magnetic stimulation (TMS) and threshold tracking nerve conduction studies (TTNCS), respectively. The study will include the recruitment of approximately 60 unmatched healthy control subjects for analysis of variability of the neurophysiological tests prior to recruitment of ALS subjects. There will also be 12 matched healthy control subjects, recruited at the same time as ALS subjects.
Interventions
DRUGEzogabine
Potiga is FDA-approved for adjunctive treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments.
DRUGPlacebo
Matched placebo
Sponsors
ALS Association
GlaxoSmithKline
Harvard University
Massachusetts General Hospital
Brian Wainger
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
ALS Subject Inclusion Criteria: * Male or female, aged 18 to 80. * Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria. * Slow vital capacity (SVC) measure ≥ 50% of predicted for gender, height and age at the Screening Visit,OR in the opinion of the SI, ability to perform and safely complete all study visit procedures. * Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at least 30 days prior to the Screening Visit and continue on the stable dose throughout the course of the study (riluzole-naïve subjects are permitted in the study). * Subjects must be able to swallow oral medication at the Screening Visit and expected to be able to swallow tablets throughout the course of the study. * Capable of providing informed consent and following trial procedures. * Geographically accessible to the site. * Women must not be able to become pregnant (e.g., post menopausal, surgically sterile, or using adequate birth control methods) for the duration of the study and three months after study completion. Adequate contraception includes: abstinence, hormonal contraception (oral contraception, implanted contraception, injected contraception or other hormonal contraception, for example patch or contraceptive ring), intrauterine device (IUD) in place for ≥ 3 months, barrier method in conjunction with spermicide, or another adequate method. * Use of medications known to affect the neurophysiology measures in the study must be scheduled, not as needed (pro re nata, PRN). A subject must have been on a fixed dose for 30 days prior to the Screening Visit, and there must be no reason to believe that a subsequent change would be necessary during the course of the study. These medications include: benzodiazepines, muscle relaxants, tricyclic antidepressants, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, hypnotics (including anti-histamines) and anti-cholinergics. * TMS shows sufficient MEP amplitude and/or NCS studies show sufficient CMAP amplitude. ALS Subject
Exclusion criteria
* Medical condition, laboratory finding, or physical exam finding that precludes participation. * Serum AST and ALT value \>2.0 times the upper normal limit * Clinically significant conduction abnormalities on electrocardiogram or a known history of cardiac arrhythmia, myocardial infarction within the past 24 months, or congestive heart failure. * Estimated glomerular filtration rate \< 50 mL/min at Screening Visit. * Concomitant digoxin treatment. * Known allergic reactions to components of the study product(s). * Exposure to any other agent currently under investigation for the treatment of patients with ALS (off-label use or investigational) within 30 days of the Screening Visit including ezogabine, exposure to cell replacement therapy within six months of the Screening Visit or any prior intraparenchymal cell replacement injection within the spinal cord or brain at anytime in the past. * Presence of tracheostomy at the Screening Visit. * History of clinically significant urinary retention, , or current use of medications to treat urinary retention. * History of drug and or alcohol abuse within 12 months of the Screening Visit. * The presence of unstable psychiatric disease, cognitive impairment, or dementia that would impair ability of the subject to provide informed consent, according to SI judgment. * Clinically significant history of unstable or severe cardiac, oncologic, hepatic, or renal disease, or other uncontrolled medical condition. * Presence of feeding tube. * Current use of antipsychotic, antiepileptic (except benzodiazepines, gabapentin, pregabalin) or class 1 (e.g. flecainide) or class 3 (e.g. amiodarone) antiarrhythmic medications. Quinidine or a quinidine-containing drug is allowed if the quinidine dose is not greater than 20 mg/day (for a full list of medications, please reference the study MOP). * Inability to perform either TMS or NCS studies due to insufficient MEP or CMAP amplitude. * Pregnant women or women currently breastfeeding. * Contraindication to TMS studies including ferromagnetic metal in the head or neck (potentially found in aneurysm clips, implanted medication pumps, implanted brain stimulators, pacemakers, cochlear implants), or history of epilepsy. Dental fillings are permitted. * Anything else that, in the opinion of the SI, would place the subject at increased risk or preclude the subject's full compliance with or completion of the study. Healthy Control Subject Inclusion Criteria: * Male or female, aged 18 to 80. * Absence of a known neurological disorder. * Capable of providing informed consent and following trial procedures. * Geographically accessible to the site. * Age (+/- 10 years and site-matched to a ALS participant within 6 months of their Baseline visit).\[Matched controls only\] * TMS shows sufficient MEP amplitude and/or NCS studies show sufficient CMAP amplitude (amplitudes defined in MOP). * Use of medications known to affect the neurophysiology measures in the study must be scheduled, not as needed (pro re nata, PRN). A subject must have been on a fixed dose for 30 days prior to the Screening Visit, and there must be no reason to believe that a subsequent change would be necessary during the course of the study. These medications include: benzodiazepines, muscle relaxants, tricyclic antidepressants, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, hypnotics (including anti-histamines) and anti-cholinergics. Healthy Control Subject
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Screening, Baseline, Week 6, Week 8 | Short-interval intracortical inhibition (SICI) or paired-pulse SICI is defined as the ratio of the response after a conditioning pulse equal to 80% of resting motor threshold (RMT) is administered 3 ms prior to the signaling pulse divided by motor evoked potential (MEP) amplitude. Transcranial magnetic stimulation (TMS) is a neurophysiologic test for assessing upper motor neuron function. Change in SICI will be assessed by transcranial magnetic stimulation (TMS) after treatment with 900 mg/day or 600 mg/day of ezogabine vs. matched oral placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in MEP Amplitude | Screening, Baseline, Week 6, Week 8 | Motor Evoked Potential (MEP) amplitude is defined as the response when a stimulus equal to 120% of Resting Motor Threshold (RMT) is administered. MEP amplitude is calculated as the geometric mean of replicate estimates. Change in MEP will be assessed by Transcranial Magnetic Stimulation (TMS). |
| Change in Duration of Cortical Silent Period | Screening, Baseline, Week 6, Week 8 | Cortical silent period (CSP) is the suppression of voluntary muscle contraction elicited by stimulation equal to 120% of resting motor threshold (RMT). CSP duration is measured from the time of the muscle activity suppression to return of muscle activity. Change in duration of cortical silent period is assessed by Transcranial Magnetic Stimulation (TMS). |
| Change in Intracortical Facilitation | Screening, Baseline, Week 6, Week 8 | Paired-pulse Intracortical facilitation (ICF) is defined as the ratio of the response after a conditioning pulse equal to 80% of Resting Motor Threshold (RMT) is administered 15 milliseconds prior to the signaling pulse divided by Motor Evoked Potential (MEP) amplitude. ICF is calculated as the geometric mean of replicate estimates. Change in intracortical facilitation is assessed by Transcranial Magnetic Stimulation (TMS). |
| Change in Electrotonus | Screening, Baseline, Week 6, Week 8 | Change in depolarizing electrotonus at 90 to 100 milliseconds was assessed by threshold tracking axonal nerve conduction studies (TTNCS). TTNCS is a neurophysiologic test for assessing lower motor neuron function. |
| Change in Strength Duration Time Constant | Screening, Baseline, Week 6, Week 8 | Assessed by threshold tracking axonal nerve conduction studies (TTNCS). |
| Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Screening, Baseline, Week 6, Week 8 | Resting Motor Evoked Potential (MEP) is the magnetic field strength, measured as a percentage of the maximum stimulator output, that produces at least a 0.05 mV response in at least 5 of 10 consecutive trials.Change in resting MEP threshold will be assessed by Transcranial Magnetic Stimulation (TMS). |
| Muscle Cramping Frequency | Week 1 through Week 10 | Frequency of muscle cramping and maximum pain from muscle cramping was collected by subjects via self-report using a daily muscle cramping diary. |
| Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Screening, Baseline, Week 4, Week 6, Week 8, Week 12 | Hand held dynamometry (HHD) will be used as a quantitative measure of muscle strength of the abductor pollicis brevis (APB) muscle. HHD will be self-report by study participants using a daily muscle cramping diary. |
| Proportion of Days With Fasciculations | Week 1 through Week 10 | For the purpose of this study, a fasciculation is a brief, spontaneous contraction affecting a small number of muscle fibers, often causing a flicker of movement under the skin. Defining interference with daily activities may be different for each subject and defining daily activities will be different for each subject. Subjects will self report by diary, days with fasciculations. |
| Number of Participants Who Tolerate Study Drug | 10 weeks | Participants will be judged tolerant of study drug if they reached their target dose and remain on study drug until planned discontinuation. Tolerability will be summarized as the proportion of participants in a treatment group who are tolerant of study drug. |
| Change in Recovery Cycle | Screening, Baseline, Week 6, Week 8 | Lower motor neuron excitability can be measured using change in recovery cycle of superexcitability. Change in recovery cycle of superexcitability after first pre-pulse is assessed by threshold tracking axonal nerve conduction studies (TTNCS). Threshold-tracking nerve conduction studies is a neurophysiologic test for assessing lower motor neuron function. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oral Ezogabine 900 mg/Day Ezogabine: Potiga is FDA-approved for adjunctive treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments. | 19 |
| Oral Ezogabine 600 mg/Day Ezogabine: Potiga is FDA-approved for adjunctive treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments. | 23 |
| Placebo Placebo: Matched placebo | 23 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 4 |
Baseline characteristics
| Characteristic | Oral Ezogabine 900 mg/Day | Total | Placebo | Oral Ezogabine 600 mg/Day |
|---|---|---|---|---|
| Age, Continuous | 58.91 years STANDARD_DEVIATION 9.1 | 58.34 years STANDARD_DEVIATION 8.78 | 58.1 years STANDARD_DEVIATION 9.55 | 57.4 years STANDARD_DEVIATION 8.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 63 Participants | 22 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 63 Participants | 23 Participants | 23 Participants |
| Region of Enrollment United States | 19 Participants | 65 Participants | 23 Participants | 23 Participants |
| Sex: Female, Male Female | 6 Participants | 20 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 13 Participants | 45 Participants | 19 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 23 | 0 / 23 |
| other Total, other adverse events | 19 / 19 | 23 / 23 | 23 / 23 |
| serious Total, serious adverse events | 1 / 19 | 2 / 23 | 0 / 23 |
Outcome results
Primary
Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS)
Short-interval intracortical inhibition (SICI) or paired-pulse SICI is defined as the ratio of the response after a conditioning pulse equal to 80% of resting motor threshold (RMT) is administered 3 ms prior to the signaling pulse divided by motor evoked potential (MEP) amplitude. Transcranial magnetic stimulation (TMS) is a neurophysiologic test for assessing upper motor neuron function. Change in SICI will be assessed by transcranial magnetic stimulation (TMS) after treatment with 900 mg/day or 600 mg/day of ezogabine vs. matched oral placebo.
Time frame: Screening, Baseline, Week 6, Week 8
Population: As a result of electrophysiologic response, good quality data was defined based on the central reader's evaluation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Screening | 1.180 Unitless | Standard Deviation 1.108 |
| Oral Ezogabine 900 mg/Day | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Baseline | 1.347 Unitless | Standard Deviation 1.662 |
| Oral Ezogabine 900 mg/Day | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Week 6 | 1.100 Unitless | Standard Deviation 1.066 |
| Oral Ezogabine 900 mg/Day | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Week 8 | 0.948 Unitless | Standard Deviation 1.169 |
| Oral Ezogabine 600 mg/Day | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Week 8 | 0.617 Unitless | Standard Deviation 0.455 |
| Oral Ezogabine 600 mg/Day | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Screening | 0.965 Unitless | Standard Deviation 1.302 |
| Oral Ezogabine 600 mg/Day | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Week 6 | 0.675 Unitless | Standard Deviation 0.613 |
| Oral Ezogabine 600 mg/Day | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Baseline | 0.952 Unitless | Standard Deviation 1.138 |
| Placebo | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Week 8 | 0.834 Unitless | Standard Deviation 0.488 |
| Placebo | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Baseline | 0.755 Unitless | Standard Deviation 0.539 |
| Placebo | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Week 6 | 0.777 Unitless | Standard Deviation 0.442 |
| Placebo | Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) | Screening | 0.784 Unitless | Standard Deviation 0.56 |
Secondary
Change in Duration of Cortical Silent Period
Cortical silent period (CSP) is the suppression of voluntary muscle contraction elicited by stimulation equal to 120% of resting motor threshold (RMT). CSP duration is measured from the time of the muscle activity suppression to return of muscle activity. Change in duration of cortical silent period is assessed by Transcranial Magnetic Stimulation (TMS).
Time frame: Screening, Baseline, Week 6, Week 8
Population: Data of low quality were removed from analysis population as a result of the central reader's evaluation standards.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Change in Duration of Cortical Silent Period | Screening | 99.542 Milliseconds | Standard Deviation 39.153 |
| Oral Ezogabine 900 mg/Day | Change in Duration of Cortical Silent Period | Baseline | 80.223 Milliseconds | Standard Deviation 23.44 |
| Oral Ezogabine 900 mg/Day | Change in Duration of Cortical Silent Period | Week 6 | 96.844 Milliseconds | Standard Deviation 43.426 |
| Oral Ezogabine 900 mg/Day | Change in Duration of Cortical Silent Period | Week 8 | 88.000 Milliseconds | Standard Deviation 32.258 |
| Oral Ezogabine 600 mg/Day | Change in Duration of Cortical Silent Period | Week 8 | 58.870 Milliseconds | Standard Deviation 21761 |
| Oral Ezogabine 600 mg/Day | Change in Duration of Cortical Silent Period | Screening | 69.273 Milliseconds | Standard Deviation 29.921 |
| Oral Ezogabine 600 mg/Day | Change in Duration of Cortical Silent Period | Week 6 | 74.917 Milliseconds | Standard Deviation 36.338 |
| Oral Ezogabine 600 mg/Day | Change in Duration of Cortical Silent Period | Baseline | 76.006 Milliseconds | Standard Deviation 30.459 |
| Placebo | Change in Duration of Cortical Silent Period | Week 8 | 87.479 Milliseconds | Standard Deviation 39.839 |
| Placebo | Change in Duration of Cortical Silent Period | Baseline | 80.638 Milliseconds | Standard Deviation 32.894 |
| Placebo | Change in Duration of Cortical Silent Period | Week 6 | 83.479 Milliseconds | Standard Deviation 32.92 |
| Placebo | Change in Duration of Cortical Silent Period | Screening | 88.831 Milliseconds | Standard Deviation 39.519 |
Secondary
Change in Electrotonus
Change in depolarizing electrotonus at 90 to 100 milliseconds was assessed by threshold tracking axonal nerve conduction studies (TTNCS). TTNCS is a neurophysiologic test for assessing lower motor neuron function.
Time frame: Screening, Baseline, Week 6, Week 8
Population: Data of low quality were removed from analysis population as a result of the central reader's evaluation standards.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Change in Electrotonus | Screening | 52.275 percentage of threshold | Standard Deviation 14.924 |
| Oral Ezogabine 900 mg/Day | Change in Electrotonus | Baseline | 46.278 percentage of threshold | Standard Deviation 7.663 |
| Oral Ezogabine 900 mg/Day | Change in Electrotonus | Week 6 | 50.187 percentage of threshold | Standard Deviation 6.645 |
| Oral Ezogabine 900 mg/Day | Change in Electrotonus | Week 8 | 50.108 percentage of threshold | Standard Deviation 2.533 |
| Oral Ezogabine 600 mg/Day | Change in Electrotonus | Week 8 | 48.552 percentage of threshold | Standard Deviation 13.422 |
| Oral Ezogabine 600 mg/Day | Change in Electrotonus | Screening | 48.144 percentage of threshold | Standard Deviation 8.636 |
| Oral Ezogabine 600 mg/Day | Change in Electrotonus | Week 6 | 51.857 percentage of threshold | Standard Deviation 7.303 |
| Oral Ezogabine 600 mg/Day | Change in Electrotonus | Baseline | 48.901 percentage of threshold | Standard Deviation 9.327 |
| Placebo | Change in Electrotonus | Week 8 | 47.010 percentage of threshold | Standard Deviation 6.212 |
| Placebo | Change in Electrotonus | Baseline | 46.574 percentage of threshold | Standard Deviation 6.689 |
| Placebo | Change in Electrotonus | Week 6 | 44.898 percentage of threshold | Standard Deviation 6.082 |
| Placebo | Change in Electrotonus | Screening | 44.532 percentage of threshold | Standard Deviation 6.666 |
Secondary
Change in Intracortical Facilitation
Paired-pulse Intracortical facilitation (ICF) is defined as the ratio of the response after a conditioning pulse equal to 80% of Resting Motor Threshold (RMT) is administered 15 milliseconds prior to the signaling pulse divided by Motor Evoked Potential (MEP) amplitude. ICF is calculated as the geometric mean of replicate estimates. Change in intracortical facilitation is assessed by Transcranial Magnetic Stimulation (TMS).
Time frame: Screening, Baseline, Week 6, Week 8
Population: Data of low quality were removed from analysis population as a result of the central reader's evaluation standards.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Change in Intracortical Facilitation | Week 6 | 1.894 Unitless | Standard Deviation 1.177 |
| Oral Ezogabine 900 mg/Day | Change in Intracortical Facilitation | Screening | 1.829 Unitless | Standard Deviation 0.862 |
| Oral Ezogabine 900 mg/Day | Change in Intracortical Facilitation | Week 8 | 1.779 Unitless | Standard Deviation 1.627 |
| Oral Ezogabine 900 mg/Day | Change in Intracortical Facilitation | Baseline | 2.420 Unitless | Standard Deviation 2.356 |
| Oral Ezogabine 600 mg/Day | Change in Intracortical Facilitation | Week 6 | 1.535 Unitless | Standard Deviation 1.472 |
| Oral Ezogabine 600 mg/Day | Change in Intracortical Facilitation | Baseline | 2.073 Unitless | Standard Deviation 2.075 |
| Oral Ezogabine 600 mg/Day | Change in Intracortical Facilitation | Week 8 | 1.466 Unitless | Standard Deviation 0.836 |
| Oral Ezogabine 600 mg/Day | Change in Intracortical Facilitation | Screening | 1.849 Unitless | Standard Deviation 1.669 |
| Placebo | Change in Intracortical Facilitation | Week 8 | 1.514 Unitless | Standard Deviation 0.817 |
| Placebo | Change in Intracortical Facilitation | Screening | 1.653 Unitless | Standard Deviation 0.907 |
| Placebo | Change in Intracortical Facilitation | Baseline | 1.531 Unitless | Standard Deviation 0.906 |
| Placebo | Change in Intracortical Facilitation | Week 6 | 1.571 Unitless | Standard Deviation 1.298 |
Secondary
Change in MEP Amplitude
Motor Evoked Potential (MEP) amplitude is defined as the response when a stimulus equal to 120% of Resting Motor Threshold (RMT) is administered. MEP amplitude is calculated as the geometric mean of replicate estimates. Change in MEP will be assessed by Transcranial Magnetic Stimulation (TMS).
Time frame: Screening, Baseline, Week 6, Week 8
Population: Data of low quality were removed from analysis as a result of the central reader's evaluation standards.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Change in MEP Amplitude | Screening | 0.639 Millivolts | Standard Deviation 0.635 |
| Oral Ezogabine 900 mg/Day | Change in MEP Amplitude | Baseline | 0.395 Millivolts | Standard Deviation 0.282 |
| Oral Ezogabine 900 mg/Day | Change in MEP Amplitude | Week 6 | 1.78 Millivolts | Standard Deviation 1.568 |
| Oral Ezogabine 900 mg/Day | Change in MEP Amplitude | Week 8 | 0.571 Millivolts | Standard Deviation 0.345 |
| Oral Ezogabine 600 mg/Day | Change in MEP Amplitude | Week 8 | 1.129 Millivolts | Standard Deviation 0.6 |
| Oral Ezogabine 600 mg/Day | Change in MEP Amplitude | Screening | 1.210 Millivolts | Standard Deviation 1.958 |
| Oral Ezogabine 600 mg/Day | Change in MEP Amplitude | Week 6 | 0.914 Millivolts | Standard Deviation 0.861 |
| Oral Ezogabine 600 mg/Day | Change in MEP Amplitude | Baseline | 0.954 Millivolts | Standard Deviation 1.402 |
| Placebo | Change in MEP Amplitude | Week 8 | 0.450 Millivolts | Standard Deviation 0.299 |
| Placebo | Change in MEP Amplitude | Baseline | 1.098 Millivolts | Standard Deviation 1.197 |
| Placebo | Change in MEP Amplitude | Week 6 | 0.454 Millivolts | Standard Deviation 0.339 |
| Placebo | Change in MEP Amplitude | Screening | 0.845 Millivolts | Standard Deviation 0.626 |
Secondary
Change in Recovery Cycle
Lower motor neuron excitability can be measured using change in recovery cycle of superexcitability. Change in recovery cycle of superexcitability after first pre-pulse is assessed by threshold tracking axonal nerve conduction studies (TTNCS). Threshold-tracking nerve conduction studies is a neurophysiologic test for assessing lower motor neuron function.
Time frame: Screening, Baseline, Week 6, Week 8
Population: Data of low quality were removed from analysis as a result of the central reader's evaluation standards.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Change in Recovery Cycle | Screening | -30.45 percentage of threshold | Standard Deviation 8.694 |
| Oral Ezogabine 900 mg/Day | Change in Recovery Cycle | Baseline | -31.39 percentage of threshold | Standard Deviation 6.896 |
| Oral Ezogabine 900 mg/Day | Change in Recovery Cycle | Week 6 | -37.59 percentage of threshold | Standard Deviation 5.066 |
| Oral Ezogabine 900 mg/Day | Change in Recovery Cycle | Week 8 | -38.20 percentage of threshold | Standard Deviation 4.965 |
| Oral Ezogabine 600 mg/Day | Change in Recovery Cycle | Week 8 | -33.15 percentage of threshold | Standard Deviation 13.874 |
| Oral Ezogabine 600 mg/Day | Change in Recovery Cycle | Screening | -28.12 percentage of threshold | Standard Deviation 8.401 |
| Oral Ezogabine 600 mg/Day | Change in Recovery Cycle | Week 6 | -37.48 percentage of threshold | Standard Deviation 7.451 |
| Oral Ezogabine 600 mg/Day | Change in Recovery Cycle | Baseline | -27.40 percentage of threshold | Standard Deviation 6.993 |
| Placebo | Change in Recovery Cycle | Week 8 | -29.26 percentage of threshold | Standard Deviation 5.88 |
| Placebo | Change in Recovery Cycle | Baseline | -28.16 percentage of threshold | Standard Deviation 7.589 |
| Placebo | Change in Recovery Cycle | Week 6 | -28.37 percentage of threshold | Standard Deviation 7.835 |
| Placebo | Change in Recovery Cycle | Screening | -27.77 percentage of threshold | Standard Deviation 7.955 |
Secondary
Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance)
Resting Motor Evoked Potential (MEP) is the magnetic field strength, measured as a percentage of the maximum stimulator output, that produces at least a 0.05 mV response in at least 5 of 10 consecutive trials.Change in resting MEP threshold will be assessed by Transcranial Magnetic Stimulation (TMS).
Time frame: Screening, Baseline, Week 6, Week 8
Population: Data of low quality may have been removed from the number of participants analyzed based on the central reader's evaluation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Screening | 51.250 percentage of the maximum output | Standard Deviation 14.379 |
| Oral Ezogabine 900 mg/Day | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Baseline | 48.385 percentage of the maximum output | Standard Deviation 14.373 |
| Oral Ezogabine 900 mg/Day | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Week 6 | 50.111 percentage of the maximum output | Standard Deviation 14.066 |
| Oral Ezogabine 900 mg/Day | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Week 8 | 46.00 percentage of the maximum output | Standard Deviation 10.876 |
| Oral Ezogabine 600 mg/Day | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Week 8 | 56.700 percentage of the maximum output | Standard Deviation 13.039 |
| Oral Ezogabine 600 mg/Day | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Screening | 52.000 percentage of the maximum output | Standard Deviation 11.48 |
| Oral Ezogabine 600 mg/Day | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Week 6 | 57.583 percentage of the maximum output | Standard Deviation 15.365 |
| Oral Ezogabine 600 mg/Day | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Baseline | 54.250 percentage of the maximum output | Standard Deviation 11.018 |
| Placebo | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Week 8 | 55.357 percentage of the maximum output | Standard Deviation 10.149 |
| Placebo | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Baseline | 57.231 percentage of the maximum output | Standard Deviation 13.498 |
| Placebo | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Week 6 | 54.714 percentage of the maximum output | Standard Deviation 12.313 |
| Placebo | Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) | Screening | 56.308 percentage of the maximum output | Standard Deviation 13.804 |
Secondary
Change in Strength Duration Time Constant
Assessed by threshold tracking axonal nerve conduction studies (TTNCS).
Time frame: Screening, Baseline, Week 6, Week 8
Population: Data of low quality were removed from analysis population as a result of the central reader's evaluation standards.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Change in Strength Duration Time Constant | Screening | 0.521 Milliseconds | Standard Deviation 0.084 |
| Oral Ezogabine 900 mg/Day | Change in Strength Duration Time Constant | Baseline | 0.522 Milliseconds | Standard Deviation 0.084 |
| Oral Ezogabine 900 mg/Day | Change in Strength Duration Time Constant | Week 6 | 0.416 Milliseconds | Standard Deviation 0.141 |
| Oral Ezogabine 900 mg/Day | Change in Strength Duration Time Constant | Week 8 | 0.341 Milliseconds | Standard Deviation 0.079 |
| Oral Ezogabine 600 mg/Day | Change in Strength Duration Time Constant | Week 8 | 0.461 Milliseconds | Standard Deviation 0.134 |
| Oral Ezogabine 600 mg/Day | Change in Strength Duration Time Constant | Screening | 0.451 Milliseconds | Standard Deviation 0.096 |
| Oral Ezogabine 600 mg/Day | Change in Strength Duration Time Constant | Week 6 | 0.480 Milliseconds | Standard Deviation 0.165 |
| Oral Ezogabine 600 mg/Day | Change in Strength Duration Time Constant | Baseline | 0.454 Milliseconds | Standard Deviation 0.084 |
| Placebo | Change in Strength Duration Time Constant | Week 8 | 0.497 Milliseconds | Standard Deviation 0.173 |
| Placebo | Change in Strength Duration Time Constant | Baseline | 0.488 Milliseconds | Standard Deviation 0.078 |
| Placebo | Change in Strength Duration Time Constant | Week 6 | 0.546 Milliseconds | Standard Deviation 0.12 |
| Placebo | Change in Strength Duration Time Constant | Screening | 0.505 Milliseconds | Standard Deviation 0.086 |
Secondary
Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis
Hand held dynamometry (HHD) will be used as a quantitative measure of muscle strength of the abductor pollicis brevis (APB) muscle. HHD will be self-report by study participants using a daily muscle cramping diary.
Time frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12
Population: Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 8 | 7.015 kilograms (kg) | Standard Deviation 4.398 |
| Oral Ezogabine 900 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 12 | 5.887 kilograms (kg) | Standard Deviation 3.696 |
| Oral Ezogabine 900 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Baseline | 6.584 kilograms (kg) | Standard Deviation 4.022 |
| Oral Ezogabine 900 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Screening | 6.721 kilograms (kg) | Standard Deviation 4.548 |
| Oral Ezogabine 900 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 4 | 6.461 kilograms (kg) | Standard Deviation 4.002 |
| Oral Ezogabine 900 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 6 | 6.838 kilograms (kg) | Standard Deviation 3.569 |
| Oral Ezogabine 600 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Screening | 8.577 kilograms (kg) | Standard Deviation 6.927 |
| Oral Ezogabine 600 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 8 | 5.633 kilograms (kg) | Standard Deviation 4.015 |
| Oral Ezogabine 600 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Baseline | 6.641 kilograms (kg) | Standard Deviation 4.901 |
| Oral Ezogabine 600 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 6 | 6.921 kilograms (kg) | Standard Deviation 5.57 |
| Oral Ezogabine 600 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 12 | 5.439 kilograms (kg) | Standard Deviation 3.609 |
| Oral Ezogabine 600 mg/Day | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 4 | 7.333 kilograms (kg) | Standard Deviation 5.839 |
| Placebo | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 12 | 5.643 kilograms (kg) | Standard Deviation 4.523 |
| Placebo | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Screening | 7.448 kilograms (kg) | Standard Deviation 4.048 |
| Placebo | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Baseline | 7.164 kilograms (kg) | Standard Deviation 4.716 |
| Placebo | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 4 | 6.686 kilograms (kg) | Standard Deviation 5.115 |
| Placebo | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 6 | 6.300 kilograms (kg) | Standard Deviation 5.167 |
| Placebo | Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis | Week 8 | 6.523 kilograms (kg) | Standard Deviation 4.523 |
Secondary
Muscle Cramping Frequency
Frequency of muscle cramping and maximum pain from muscle cramping was collected by subjects via self-report using a daily muscle cramping diary.
Time frame: Week 1 through Week 10
Population: Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Muscle Cramping Frequency | Week 4 | 12.018 Days | Standard Deviation 18.824 |
| Oral Ezogabine 900 mg/Day | Muscle Cramping Frequency | Week 1 | 12.176 Days | Standard Deviation 15.233 |
| Oral Ezogabine 900 mg/Day | Muscle Cramping Frequency | Week 2 | 9.235 Days | Standard Deviation 11.729 |
| Oral Ezogabine 900 mg/Day | Muscle Cramping Frequency | Week 3 | 10.906 Days | Standard Deviation 13.532 |
| Oral Ezogabine 900 mg/Day | Muscle Cramping Frequency | Week 5 | 12.533 Days | Standard Deviation 15.824 |
| Oral Ezogabine 900 mg/Day | Muscle Cramping Frequency | Week 6 | 11.033 Days | Standard Deviation 11.705 |
| Oral Ezogabine 900 mg/Day | Muscle Cramping Frequency | Week 7 | 9.400 Days | Standard Deviation 10.716 |
| Oral Ezogabine 900 mg/Day | Muscle Cramping Frequency | Week 8 | 11.211 Days | Standard Deviation 13.521 |
| Oral Ezogabine 900 mg/Day | Muscle Cramping Frequency | Week 9 | 12.786 Days | Standard Deviation 14.154 |
| Oral Ezogabine 900 mg/Day | Muscle Cramping Frequency | Week 10 | 13.179 Days | Standard Deviation 14.953 |
| Oral Ezogabine 600 mg/Day | Muscle Cramping Frequency | Week 9 | 9.933 Days | Standard Deviation 11.75 |
| Oral Ezogabine 600 mg/Day | Muscle Cramping Frequency | Week 6 | 8.333 Days | Standard Deviation 10.887 |
| Oral Ezogabine 600 mg/Day | Muscle Cramping Frequency | Week 1 | 8.738 Days | Standard Deviation 14.477 |
| Oral Ezogabine 600 mg/Day | Muscle Cramping Frequency | Week 5 | 10.265 Days | Standard Deviation 13.404 |
| Oral Ezogabine 600 mg/Day | Muscle Cramping Frequency | Week 8 | 9.067 Days | Standard Deviation 11.151 |
| Oral Ezogabine 600 mg/Day | Muscle Cramping Frequency | Week 2 | 7.083 Days | Standard Deviation 11.558 |
| Oral Ezogabine 600 mg/Day | Muscle Cramping Frequency | Week 10 | 10.188 Days | Standard Deviation 12.296 |
| Oral Ezogabine 600 mg/Day | Muscle Cramping Frequency | Week 7 | 9.714 Days | Standard Deviation 12.755 |
| Oral Ezogabine 600 mg/Day | Muscle Cramping Frequency | Week 3 | 7.750 Days | Standard Deviation 12.268 |
| Oral Ezogabine 600 mg/Day | Muscle Cramping Frequency | Week 4 | 9.135 Days | Standard Deviation 12.664 |
| Placebo | Muscle Cramping Frequency | Week 3 | 10.170 Days | Standard Deviation 13.915 |
| Placebo | Muscle Cramping Frequency | Week 4 | 106.19 Days | Standard Deviation 14.016 |
| Placebo | Muscle Cramping Frequency | Week 5 | 8.955 Days | Standard Deviation 13.268 |
| Placebo | Muscle Cramping Frequency | Week 6 | 8.539 Days | Standard Deviation 10.869 |
| Placebo | Muscle Cramping Frequency | Week 9 | 11.190 Days | Standard Deviation 16.162 |
| Placebo | Muscle Cramping Frequency | Week 7 | 9.609 Days | Standard Deviation 12.551 |
| Placebo | Muscle Cramping Frequency | Week 10 | 13.600 Days | Standard Deviation 16.162 |
| Placebo | Muscle Cramping Frequency | Week 1 | 9.536 Days | Standard Deviation 15.909 |
| Placebo | Muscle Cramping Frequency | Week 2 | 8.273 Days | Standard Deviation 10.968 |
| Placebo | Muscle Cramping Frequency | Week 8 | 9.282 Days | Standard Deviation 12.244 |
Secondary
Number of Participants Who Tolerate Study Drug
Participants will be judged tolerant of study drug if they reached their target dose and remain on study drug until planned discontinuation. Tolerability will be summarized as the proportion of participants in a treatment group who are tolerant of study drug.
Time frame: 10 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Ezogabine 900 mg/Day | Number of Participants Who Tolerate Study Drug | 14 Participants |
| Oral Ezogabine 600 mg/Day | Number of Participants Who Tolerate Study Drug | 11 Participants |
| Placebo | Number of Participants Who Tolerate Study Drug | 23 Participants |
Secondary
Proportion of Days With Fasciculations
For the purpose of this study, a fasciculation is a brief, spontaneous contraction affecting a small number of muscle fibers, often causing a flicker of movement under the skin. Defining interference with daily activities may be different for each subject and defining daily activities will be different for each subject. Subjects will self report by diary, days with fasciculations.
Time frame: Week 1 through Week 10
Population: Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Ezogabine 900 mg/Day | Proportion of Days With Fasciculations | Week 1 | 0.918 Proportion of Days | Standard Deviation 0.134 |
| Oral Ezogabine 900 mg/Day | Proportion of Days With Fasciculations | Week 2 | 0.918 Proportion of Days | Standard Deviation 0.229 |
| Oral Ezogabine 900 mg/Day | Proportion of Days With Fasciculations | Week 3 | 0.796 Proportion of Days | Standard Deviation 0.366 |
| Oral Ezogabine 900 mg/Day | Proportion of Days With Fasciculations | Week 4 | 0.752 Proportion of Days | Standard Deviation 0.352 |
| Oral Ezogabine 900 mg/Day | Proportion of Days With Fasciculations | Week 5 | 0.879 Proportion of Days | Standard Deviation 0.285 |
| Oral Ezogabine 900 mg/Day | Proportion of Days With Fasciculations | Week 6 | 0.868 Proportion of Days | Standard Deviation 0.288 |
| Oral Ezogabine 900 mg/Day | Proportion of Days With Fasciculations | Week 7 | 0.912 Proportion of Days | Standard Deviation 0.277 |
| Oral Ezogabine 900 mg/Day | Proportion of Days With Fasciculations | Week 8 | 0.868 Proportion of Days | Standard Deviation 0.294 |
| Oral Ezogabine 900 mg/Day | Proportion of Days With Fasciculations | Week 9 | 0.893 Proportion of Days | Standard Deviation 0.293 |
| Oral Ezogabine 900 mg/Day | Proportion of Days With Fasciculations | Week 10 | 0.869 Proportion of Days | Standard Deviation 0.319 |
| Oral Ezogabine 600 mg/Day | Proportion of Days With Fasciculations | Week 9 | 0.657 Proportion of Days | Standard Deviation 0.472 |
| Oral Ezogabine 600 mg/Day | Proportion of Days With Fasciculations | Week 1 | 0.659 Proportion of Days | Standard Deviation 0.415 |
| Oral Ezogabine 600 mg/Day | Proportion of Days With Fasciculations | Week 6 | 0.714 Proportion of Days | Standard Deviation 0.438 |
| Oral Ezogabine 600 mg/Day | Proportion of Days With Fasciculations | Week 5 | 0.659 Proportion of Days | Standard Deviation 0.461 |
| Oral Ezogabine 600 mg/Day | Proportion of Days With Fasciculations | Week 2 | 0.637 Proportion of Days | Standard Deviation 0.435 |
| Oral Ezogabine 600 mg/Day | Proportion of Days With Fasciculations | Week 10 | 0.700 Proportion of Days | Standard Deviation 0.483 |
| Oral Ezogabine 600 mg/Day | Proportion of Days With Fasciculations | Week 8 | 0.688 Proportion of Days | Standard Deviation 0.46 |
| Oral Ezogabine 600 mg/Day | Proportion of Days With Fasciculations | Week 3 | 0.648 Proportion of Days | Standard Deviation 0.439 |
| Oral Ezogabine 600 mg/Day | Proportion of Days With Fasciculations | Week 7 | 0.767 Proportion of Days | Standard Deviation 0.417 |
| Oral Ezogabine 600 mg/Day | Proportion of Days With Fasciculations | Week 4 | 0.637 Proportion of Days | Standard Deviation 0.45 |
| Placebo | Proportion of Days With Fasciculations | Week 8 | 0.714 Proportion of Days | Standard Deviation 0.432 |
| Placebo | Proportion of Days With Fasciculations | Week 4 | 0.806 Proportion of Days | Standard Deviation 0.348 |
| Placebo | Proportion of Days With Fasciculations | Week 5 | 0.733 Proportion of Days | Standard Deviation 0.374 |
| Placebo | Proportion of Days With Fasciculations | Week 6 | 0.765 Proportion of Days | Standard Deviation 0.418 |
| Placebo | Proportion of Days With Fasciculations | Week 9 | 0.857 Proportion of Days | Standard Deviation 0.296 |
| Placebo | Proportion of Days With Fasciculations | Week 7 | 0.786 Proportion of Days | Standard Deviation 0.379 |
| Placebo | Proportion of Days With Fasciculations | Week 1 | 0.745 Proportion of Days | Standard Deviation 0.368 |
| Placebo | Proportion of Days With Fasciculations | Week 10 | 0.813 Proportion of Days | Standard Deviation 0.38 |
| Placebo | Proportion of Days With Fasciculations | Week 2 | 0.776 Proportion of Days | Standard Deviation 0.325 |
| Placebo | Proportion of Days With Fasciculations | Week 3 | 0.816 Proportion of Days | Standard Deviation 0.334 |