Clinical Trial of Ezogabine (Retigabine) in ALS Subjects

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.

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.