Clinical Trial of Ezogabine (Retigabine) in ALS Subjects

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2 Pharmacodynamic Trial of Ezogabine (Retigabine) on Neuronal Excitability in Amyotrophic Lateral Sclerosis

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Ezogabine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 Exclusion Criteria: History of ALS or other neurodegenerative disease. Presence of positive family history of ALS. Current use of an antipsychotic or antiarrhythmic medication Definitely or possibly pregnant. 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral ezogabine 600 mg/day<br> | Drug: Ezogabine<br>* 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.<br>* Other names: Retigabine;|
| Experimental: Oral ezogabine 900 mg/day<br> | Drug: Ezogabine<br>* 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.<br>* Other names: Retigabine;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Matched placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Screening, Baseline, Week 6, Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Screening, Baseline, Week 6, Week 8 | 
| 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). | Screening, Baseline, Week 6, Week 8 | 
| 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). | Screening, Baseline, Week 6, Week 8 | 
| 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). | Screening, Baseline, Week 6, Week 8 | 
| 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. | Screening, Baseline, Week 6, Week 8 | 
| Change in Strength Duration Time Constant | Assessed by threshold tracking axonal nerve conduction studies (TTNCS). | Screening, Baseline, Week 6, Week 8 | 
| 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. | Screening, Baseline, Week 6, Week 8 | 
| 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. | Week 1 through Week 10 | 
| 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. | Screening, Baseline, Week 4, Week 6, Week 8, Week 12 | 
| 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. | Week 1 through Week 10 | 
| 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. | 10 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyotrophic Lateral Sclerosis, ALS, Lou Gehrig