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

Study Purpose:

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.

Disease:

Amyotrophic Lateral Sclerosis (ALS),  Familial ALS,  Sporadic ALS, Healthy Volunteer

Study Type:

Interventional Trial

Study Category:

Drug Trial

Study Status:

Active, currently recruiting

Phase:

Phase II

Study Chair(s)/Principal Investigator(s):

Brian J. Wainger, M.D., PhD (MGH-NCRI)
Merit Cudkowicz, M.D. M. Sc. (MGH-NCRI)

Clinicaltrials.gov ID (11 digit #):

NCT02450552

Neals Affiliated?

Yes

Coordinating Center Contact Information

Mass General Hospital - Neurological Clinical Research Institute
Lindsay Pothier / .(JavaScript must be enabled to view this email address) / 617-643-5582
Armineuza Evora / .(JavaScript must be enabled to view this email address) / 617-724-5984
165 Cambridge Street
Suite 600
Boston, Massachusetts 02114 United States

Full Study Summary:

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.

Study Sponsor:

ALS Association (ALSA), GlaxoSmithKline (GSK), Harvard Stem Cell Institute (HSCI), Neurological Clinical Research Institute (NCRI)

Participant Duration:

The total study duration is approximately 14 weeks. ALS subjects will take study drug for approximately 10 weeks.

Estimated Enrollment:

192 (120-ALS Subjects, 60 Health Controls, 12 Matched Health Controls)

Estimated Study Start Date:

06/01/2015

Estimated Study Completion Date:

02/28/2018

Posting Last Modified Date:

08/16/2017

Date Study Added to alsconsortium.org:

05/27/2015
  • Eligibility Criteria

    Gender:

    Female, Male

    Minimum Age:

    18

    Maximum Age:

    80

    Min Vital Capacity (% predicted normal):

    50

    Time since Symptom Onset:

    N/A

    Time since Diagnosis:

    N/A

    Can participants use Riluzole?

    Yes


    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.

  • Site Contact Information

    Augusta University
    Brandy Quarles / .(JavaScript must be enabled to view this email address) / 706-721-2681
    Kristy Bouchard / .(JavaScript must be enabled to view this email address) / 706-721-2681
    Georgia Regents Medical Center
    Augusta, Georgia 30912
    United States

    Barrow Neurological Institute
    Nicole Turcotte / .(JavaScript must be enabled to view this email address) / 602-406-4775
    Fulton ALS Center
    Phoenix, Arizona 85013
    United States

    Beth Israel Deaconess Medical Center
    Carmen Shin / .(JavaScript must be enabled to view this email address) / 617-667-4249
    Maria Martucci / .(JavaScript must be enabled to view this email address) / 617-667-3053
    435 Kirstein Building, Floor 4
    Boston, Massachusetts 02215
    United States

    Cedars-Sinai Medical Center
    Dana Fine / .(JavaScript must be enabled to view this email address) / 310-423-8497
    Vy Nguyen / .(JavaScript must be enabled to view this email address) / 424-315-2361
    127 S. San Vincente Blvd.
    Los Angeles, California 90048
    United States

    Duke University Medical Center
    Karen Grace / .(JavaScript must be enabled to view this email address) / 919-668-2844
    932 Morrene Road
    Durham, North Carolina 27705
    United States

    Hospital for Special Surgery
    Shara Holzberg / .(JavaScript must be enabled to view this email address) / 212-774-2361
    Megan Parmenter / .(JavaScript must be enabled to view this email address) / 646-797-8657
    525 East 71st Street
    New York, New York 10021
    United States

    Johns Hopkins Hospital
    Kristen Riley / .(JavaScript must be enabled to view this email address) / 410-955-8511
    Alpa Uchil / .(JavaScript must be enabled to view this email address) / 410-955-8511
    601 N. Carolina Street
    Baltimore, Maryland 21287
    United States

    Mass General Hospital
    Mehdi Husain / .(JavaScript must be enabled to view this email address) / 617-643-2499
    165 Cambridge Street
    Boston, Massachusetts 02114
    United States

    Mayo Clinic - Jacksonville
    Arijana Draganovic / .(JavaScript must be enabled to view this email address) / 904-953-3522
    Pam Desaro / .(JavaScript must be enabled to view this email address) / 904-953-7720
    4500 San Pablo Road
    Jacksonville, Florida 32224
    United States

    Penn State College of Medicine
    Jennifer Crossen / .(JavaScript must be enabled to view this email address) / 717-531-0003
    Hershey, Pennsylvania 17033
    United States

    University of California Irvine
    Veena Mathew / .(JavaScript must be enabled to view this email address) / 714-456-2864
    Marie Wencel / .(JavaScript must be enabled to view this email address) / 714-456-6526
    200 S. Manchester Ave.
    Orange County, California 92868
    United States

    University of Michigan Medical Center
    Jayna Duell / .(JavaScript must be enabled to view this email address) / 734-763-9037
    Blake Swihart / .(JavaScript must be enabled to view this email address) / 734-763-7275
    4019 AAT-BSRB
    Ann Arbor, Michigan 48109
    United States