Clinical Trial of Ezogabine (Retigabine) in ALS Subjects
Condition: Amyotrophic Lateral Sclerosis
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis
Intervention: Ezogabine; Placebo
Intervention description: 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.; Matched placebo
Intervention MeSH terms: Ezogabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 65.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Amyotrophic Lateral Sclerosis; ALS; Lou Gehrig

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.
    

Eligibility 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 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.